The simple and comfortable design of this mouse makes it very nice to use and puts it at a nice price point. I have not noticed any hand fatigue from using this mouse. Of all the mice makes/brands that I've tried, Microsoft seems to put the most effort into ergonomics. I have been a long time Logitech user, but Microsoft mice just seem to fit my hand better and cause less fatigue. As mice technology has reached a point where the playing field is fairly even, ergonomics has become the deciding factor for me when making a purchase.
The five buttons, particularly the navigational 'back' and 'forward' buttons are a must if you dislike having to click on the 'back' arrow in your browser. My only complaint about this particular mouse is that those two buttons do not have as good a tactile feel as the Logitech's I've used in the past. The main left and right mouse buttons also have a bit of resistance to being clicked, but it isn't enough to be an annoyance.
Overall, this is a great mouse and would buy it again if I needed another mouse.