While doing a little Ajax web programming, I hit this javascript error that stumped me longer than I care to admit. Unfortunately the javascript error doesn't tell you which dropdown has the multiple selection, so not a trivial one to debug if you have several controls in the mix.
Error: "Sys.WebForms.PageRequestManagerServerErrorException: Cannot have multiple items selected in a DropDownList."
I was changing the selected values based on other activity in the form. Because I was using AJAX (which uses Javascript to do the magic), not your typically web request that would re-populating the drop down list all over again on the server side, I was causing the error by using the code below. Note: the drop down list remembered the selected item from the last web request. Setting the selected property of one item, doesn't clear the other selected flags.
foreach (ListItem ...