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Spoilers!

In Act 3 where you can fight Letho, I was wondering why my sword strikes were only taking about three pixels of health away every time. I must have died ten times and quit out of boredom.

This morning I tried again, and noticed that the sword Geralt was using is a basic steel sword and not my awesome runed Caerme, and sure enough, when I looked in my inventory I found that the game had unequipped my steel sword, and I was attacking Letho with the steel sword slot completely empty. After re-equipping Caerme, the battle was much much easier.

I have noticed this happening (steel sword unequipping itself) throughout the game, often after cutscenes.