Luffy, I can't see dying. Even at the end of one piece. He'll be ready to be executed like Gol D. Roger, but his crew will charge in to save him. The manga could end there, without a conclusion. That's the closest thing to a Luffy death I can see happening.

The most devastating strawhat to be killed off...
Either Nami or Chopper.

Both are vital to the voyage itself, ignoring fighting enemy crews, since none of the others can navigate or know enough medicine to treat the guys after their battles. Luffy, Usopp and Sanji had never even been sick when Nami went down with the disease on the way to Alabasta.
Also I factor'd in that these two would have the most shock value.
Usopp, whilst a part of the weak trio, can take a nuclear explosion to the face and shrug it off with some comical face faults. Chopper, especially in cute form, being killed off would pretty much shock the fans. I don't think it'll happen however due to Chopper being One Piece's merchandise mascot.

Nami, because she's the closest to a helpless damsel we're going to get this side of Vivi, and for some reason, pain always seems that much more real when it's Nami or Robin taking a beating rather than the guys.
Again unlikely, seeing as how Oda likes Nami a lot.

Course for all I know Zoro might kick the bucket, after he achieves his goal of becoming the greatest swordsman in the world. Goes and see's Kuina in the afterworld or something similar that sounds like it's right out of a cheesy fanfic.