There is an optional hardcore mode, the character needs to drink water, ammo has weight, healing isn't instant etc. Normal mode is more similar to Fallout 3 gameplay.
The storyline is focused on the New California Republic vs. Caesar's Legion vs. New Vegas residents.
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Bartering is not just lower prices but negotiating for better rewards.
Followers can be managed through a context-sensitive menu, with orders like "follow", "stay" or "attack".
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There is a Reputation system in adition to Karma.