This is just my two cents on how a RE game would be run.
- Don't stray into the mystical. RE is famous for making sure that its stuff always seemed possible, if not necessarily believeable. It was never a demon, or black magic; it was always due to a virus and wicked experimentation. You may be tempted to surprise players by pulling out something divine or arcane in nature where they just expect it to be all-too natural. Resist this urge.
- This raises the mire of are the zombies encountered in the game really undead? Technically, they're alive, and can be killed be methods other than a shot in the head, so you may want to rethink the issue of making them standard, Undead-type zombies. Or perhaps not, since the difference can be minimal (though still there, e.g. Crimson-head zombies). Other creatures should probably be Aberrations, with the Tyrant monsters (Tyrant, Tyrant-Retriever, Prototype, Nemesis, etc.) being somewhat golem-like in nature.
- One issue worth thinking about is the nature of the viral infection. In the novels, comics, and even that movie (which I can't resist saying I disliked), it was always held that creatures made by or infected by the T-virus could infect other creatures they injured, and once you were infected, there was very, very little chance of curing yourself, since anti-viruses were extremely few and far between, requiring incredible amounts of work to get in the short time before the T-virus catalyzed. The games deliberately didn't go this route because its impossible to get through the games without taking a hit. Likewise, it may be impossible to get through an RPG of RE without taking a hit, so you might want to rethink that too.
- Don't be afraid of making the monsters damn tough. RE's genre is Survival Horror, not Badass Hero Horror. The purpose isn't to try and kill every monster you defeat, its to stay alive and get out (and, in the end, stop the infection from spreading, but this is usually done by blowing up a large area after you've left it). Keep ammo and healing supplies present, but low, forcing them to be conserved, and make the monsters that much stronger than the heroes, so that if they try and stand and fight, they will surely die. It's a quick way to make your players be frightened when something comes around the corner.
- Develop a good background for the series before you begin. Play the games, read the books and even the comics. Be familiar with the various viruses it has (the Mother Virus, T Virus, G Virus, T-Veronica Virus, X Virus, and Progeny Virus). Perhaps your characters will be contacted by the mysterious Mr. Trent from the novels, things like that.
- Keep the mood gritty and grim. Although it lacks supernatural horror, RE's survival horror feel is very Lovecraftian in nature. Play up feelings of isolation, powerlessness, and unknown fear. Have some recurring NPC's (who are average people like them) die horribly, perhaps by mutating into a monster the PCs must kill. When an adventure is over, the characters should let out a collective sigh of relief and be very happy to have escaped with their lives, and thats it. The big bad guys are still out there, faceless men at the top of a corporation with it's tentacles everywhere, undauntedly having more scientists make more horrors just waiting to be unleashed on an unsuspecting world...
