-Wooden doors, or any doors really, are completely unaffected by missles. You cannot use explosives of any kind to "blow open a door", whereas in fallout 2 that was almost always an option. Every character i play has to be a master thief, master scientist and master doctor unfortunately...
-Raiders with base ball boats have no reservations about charging someone wearing power armor with a mini gun. Literally nobody takes into account the armor or weapons you are using.
-Enclave advanced power armor MK2, the best power armor you could get in fallout 2, is worse than the T-51B armor you get in fallout 3 from the broken steel DLC. Incidentally power armor used by the BOS in FO2 was called the T-51B, but both outcast and BOS power armor in FO3 is worse than the T-51B. The T-51B doesn't raise your strength either, oddly enough.
-People can tell what gender/who you are in power armor even though they can't see your face or anything.
-Mason's log entries in the citadel tell you how one of his men wore a power armor suit that protected him completely from radiation, but power armor ingame gives you very little radiation protection.
-Sticky in Little Lamplight says that Big Town is east of lamplight. This is very very inaccurate. And lets not forget he is programmed to attack giant radscorpions with his fists even though he asked you to escort him.
-You can kill everyone in a house, but their bed and items are still owned and you cannot take them without it being considered stealing. However you can loot items freely from raider camps and even rob the citadel blind with no problems.
-Even if you kill Burke, he will still send hitmen after you, as evidenced by the contract note you find on one of the hitmen bodies.
-You can't tell Alistair you killed Burke, or ask him about the contract out on your head, or offer to blow up megaton for him directly.
-Even if everyone in tenpenny towers dies, is forced to leave, etc, you STILL cannot claim the suite there for your own.
-Somehow, Lyons managed to clear out the pitt, despite the fact that power armor in FO3 offers you so little protection that BOS soldiers regularly get killed by raiders or super mutants with assault rifles.
-Sometimes, you may enter an area to find rival factions fighting each other have killed each other, but all the bodies have been looted. Yet the loot is never to be found(not even on the survivor's bodies, even though that would be the logical place for the loot to go). E.G. If enclave soldiers are killed by feral ghouls in the jefferson memorial tunnels, their power armor and weapons can be looted but will simply vanish into thin air.
-If you show up in outcast/BOS armor, outcasts/BOS NPCs have no special reaction to it, except the scripted ones at the Outcast Outpost(Operation Anchorage DLC), instead they will simply refer to you as wastelander or call you by name.
-If you complete the anchorage DLC, you can't tell Casadin about it.
-Frag grenades do so little damage that you can take off all your armor and easily survive multiple of them blowing up at your feet. In fallout 2 frag grenades did major damage to most enemies and would send enemies flying.
-Certain items can't be repaired by yourself, but NPCs can even though there are no spare parts for the unique gauss rifle for example(which also means nobody bothers to use it...). Moria from megaton also has more repair skill than BOS scribes, the very same guys who maintain power armor, whom only have a repair skill of 19. The shady hat cannot be repaired using pre-war hats, even though they look pretty much the same.
-You cant purify dirty water using the water processing plant in megaton, even though thats the entire point of the plant.
-Jingwei's shocksword is essentially a shiskebab that is a pain to repair because chinese officer swords are rare while you can simply make an infinite amount of shiskebabs using the work bench
-You can get the robo-doc in the citadel to heal you, but not heal your radiation. I wonder what they do when one of the soldiers gets radiation poisoning from fighting centaurs...? Even random wasteland doctors can heal your radiation...
-You can't offer to help Daring in tenpenny towners look for Argyle, or even ask him where rockpolis is. There is no ingame way to "find" rockpolis without stumbling onto it apparently(there are no clues or directions listed anywhere ingame that i can find). Also you cant tell him what happened to Argyle if you take care of the ghouls for some reason.
-You get negative karma for killing the tenpenny tower ghouls, despite them telling you pointblank they intend to storm the tower and kill everyone there to take it over. You also get negative karma if you kill the ghouls after you help them reach a diplomatic solution and murder all the humans there.
-Amata doesnt blame you for killing the hostile vault 101 security guard that attacks you first(or all the guards that attacked you during your escape...), but she blames you for killing the new overseer that attacks you first. Whoah, hypocrite much?
-Braun can't log out of the simulation, but you can. It's never really explained why. The failsafe also doesn't target you or the dog either, despite it specifically meant to kill everyone in the sim. if you punch braun after activating the failsafe and after he tells you he doesn't have any power anymore, he can still instant kill you.
-You can't re-lock doors that you unlocked.
-If you attack someone, everyone in the map goes hostile even if they had no way of knowing what you did. Is this the FO3 version of "Stop right there criminal scum!"?
-If you find vault 87 before reaching that part of the main quest, you cannot in any way ask the lamplight NPCs anything about the vault. At all.
-Even if you are wearing power armor, environmental suits, or anything that would protect you from harmful gases, you are still affected by the vault 106 gas.
-Even if you kill amata's father during the scape, amata will repeatedly say that her father is still the overseer when you go back to the vault when talking to other NPCs.
-The BOS soldiers defending the GNR building will refuse to fight when the behemoth is triggered, apart from Lyon's squad. The ones on the balcony will crouch and hide behind the railing.
-A laser rifle will slow down your movement dramatically, even if holstered, much like how a missle launcher does. However an assault rifle of around the same size/weight does not.
-Even with head/sensors crippled, enemies never have any problems finding you. On the other hand you can't even see straight when YOUR head is crippled...
-If you kill zimmer, Victoria Watts simply keeps asking you to give the android component to zimmer instead of acknowledging that the quest is over.
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