The tiny info boxes and slow scrolling for items in inventory/shops (fixed by mod)
The large text in inventory that cuts off half the item description
The lack of a minimap north marker or a way to lock the minimap to north=up (fixed by mod)
The frustratingly slow meditation thing for drinking potions (and that the obvious way for drinking potions - doubleclicking in inventory - just gives a "this action cannot be performed" message rather than a "hey go to meditation" message).
The talents screen not showing what the second level of a talent does until you've taken the first level - also no indication of why you can't take the advanced trees at the start, and no indication of which talents are mutable until you take them.
No obvious list of key bindings in-game unless you already know to press "j", and having to exit the game to change the bindings - also no way of using mouse-wheel scroll
No in-game graphics options
Really awful savegame system (especially for a game that's so hard that you need to be saving all the time)
The journal's tutorial entries are very lacking, including no description whatsoever of what two of the signs do (at least well into act 1)
The alchemy screen is a complete mess - it often defaults to using your most precious ingredients (and resets to them after each potion you make), it won't tell you how many of an actively-chosen ingredient you have, it doesn't show you how many of any given potion you already have, it rotates the ingredient symbols in the middle bit so you can't tell the upright-line symbol from the diagonal-line symbol etc
You have to exit every sub-screen to go to another, rather than going eg straight from character to inventory
Tutorial messages pop up way too briefly and at really inopportune times
The zoomed-out map has no translation for the runes and has no current-location marker; the map gives very little "visited places of interest" information
Picking ingredients requires more clicks than necessary, and doesn't show its active component (hydragenum or whatever)
The delay for looting corpses is way too long, and very difficult to see the loot drop in long grass/swamp etc unless you use the medallion (which itself has an excessively-long delay)
Skipping cutscenes is very temperamental
There's probably more but that's what I can think of at the moment. Some of them are minor, others - like the alchemy/potions thing and not showing second-level talent info - are pretty damn annoying.