I have just tracked down the Nthbug in my application that I can blame ASP.Net Ajax for. To be rather exact, I can blame ASP.Net Ajax performance, and to be absolutely clear, I am talking about initialization performance.
The main issue is that I keep running into is that it takes human noticable time for the extended behaviors to be set on the page. By human noticable time I means over a second. The immediate result is that users are able to interact with the page in unexpected ways. Leading to all sorts of reported bugs that are plain impossible to reproduce unless you are aware of it.
Case in point, I have a link that point to a page, and on that link, I have defined the ModalPopupExtender. In the popup, the user is expected to fill some values, after which it will post to the next page. Imagine my surprise when I get a bug report saying that the next page showing an error about missing details. I tested it, the QA tested it, everything seemed to work, but the bug kept popping up every now and then.
It took a while to understand that the key difference was how soon the link was pressed after the page was loaded. The QA saying "and now I am going to press this link" was usually just enough for ASP.Net Ajax to initialize itself correctly.