Depends on the situation. The Hardcore mode for me is a must, since I like my fallout games to be as immersive and "realistic" as possible. As for the actual difficulty, I always use damage multiplier mods, so it doesn't really matter. Back when I played the game unmodded, I think I played it on hard difficulty. If I went up from that, those damn bullet sponges made me want to throw my controller to the moon...
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