Depends. For example, take the Companions radiant quest, Hired Muscle. Farkas chooses his quest target well in advance of you getting the quest; his choice is, technically, a quest NPC. If the NPC is normally killable, its "quest NPC" status does not protect it.
In the worst case, if that NPC dies before you get Hired Muscle, you get the quest and can never complete it.
If you get the quest while the target is still alive, there's a stage 30 (fail) if you kill the target, AND a stage 40 (fail) if the target dies before you can engage.
Also, in the Thieves Guild, Fishing Job has a staqe 250 (fail) either for getting jailed, giving up, or killing the mark. (Not to mention the fact that the quest can pick targets that are immune to pickpocketing, thus forcing you to fail.)