I've been dying to start playing this for a good year now, so I'm finally going to grab a copy. My question is simply do I have to start with the 'base-set' box, or can any of the larger box sets be used without the base box, for example 'Lair of the Wyrm' or 'The Trollfens'.
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You'll need to have the base set. The expansions are just that. No rules, no dice, only a few cards to add to the base set.
The base game is required as it provides certain "core components" which are used in every game.
The expansions only provide "additional" components, which complement or replace certain but not all core components. You can however, start with a different campaign in descent 2nd edition.
The general opinion is, that the later campaign books were more balanced, had more story and provided more overall flavor. So if you buy a big box expansion (which come with their own campaigns) you could delve straight into those. The campaigns may be slightly more complicated, as story events mess with some rules, so maybe 1-2 "test games" may be advised to start ANY campaign to ensure that no "beginner mistakes" are made in the first couple of games, which could screw the entire campaign.
Furthermore, all expansions are compatible with each other, so you don't need to buy anything "in order". Just buy whatever seems most interesting for you.