I'm on my second play through. I used the hotel room as my main player housing the first play through without issue. I'm currently using it again until I get to the strip to set up shop. I always store all my bullet crafting parts, papers (lottery tickets, etc.) and playing cards in the safe. I just returned to drop off somethings for the third or fourth time and the safe was empty. I'm assuming glitch, not in game theft. Not the end of the world, it wasn't my guns cabinet or clothes closet, but I guess the safe is un-safe for storage.

i had similar problem with the ps3 version in a diffrent town were i stored stuff and certian things like ammo i had stored up was completly gone poof and even items that the followers had and they wouldn't have later on? this is just 1 of the many problems with this new fallout game if i knew had even more problem in the game i would never bought it in the first place.

I've been leaving some stuff I don't care about in the safe to see if this was a real issue or just something I imagined. I stopped back last night to drop some stuff off and check the safe and sure enough everything in the safe was gone.

One thing I found about playing cards is .. if take them out of your inventory and put them in something.. they will disappear. But if you play a game of caravan all the cards you've purchased will still be there. I now use it as a way to get rid of the cards listed and cluttering up my characters inventory. Buy, discard, still there. I'm assuming that maybe they aren't supposed to show up in your inventory anyway. I mean it's kind of silly for them to be individually listed there.
The other things I store in the safe are gun mods, money and stealthboys. I've never had any of those items disappear.

I stored NCR dollars, Legion Denarius and Pre-War Money in that safe.

Never had it reset. Maybe it was stolen

Did you actually rent the room or receive it rent free from Cliff? I could see this happening if you used it without being given permission by an NPC to use it.

fail. you can store all your items on a dead npc,random toolbox and come back weeks later and it will still be there,Npcs cant steal items,unless they are unarmed and attacked right infront of where you have items stored..so yeh glitch,same thing would happen in fo3,had my whole house in megatonne get cleaned out.got paranoid and started planting land mines in my own house incase the theif returned,but yeh didnt happen =(

I've only stored things like teddy bears and toy cars in my room at the Novac motel, not used the safe, so thanks for the warning.
The mines thing is something I would have done too!