For me one of the biggest misfires is the way Jadzia's death was handled. I like that she died because I feel it was a good opportunity to explore the Trill...but the way she died was so anticlimactic.
My opinion for the worst misfire is the fact that Damar dies. Again, anticlimactically, but in this case it just felt like the writers discarded a character who had received one of the most subtle, interesting and important arcs in the show right at the last moment. It felt like leaving things open to focus on Garak but I think that could still have been done without unnecessarily killing off Damar. I wanted him to be there to rebuild Cardassia, that was where his arc beautifully and naturally led, but alas..