Just discovered the solution to this, and since I'd not managed to find it online when I was struggling with it, wanted to share for the benefit of others: I experienced a number of issues trying to get RadAsyncUpload to work, and just when I thought I'd got everything sorted, I ran into a new issue on the live server (but not local dev): for files over 2MB, the upload would start, but then fail at exactly 2048Kb; Firebug helped me to discover that it was the second POST to Telerik.Web.UI.WebResource.axd?type=rau that was returning a 500 error; after having gone through all the suggested troubleshooting etc. during earlier phases, I was left to my own devices to figure this one out - thankfully it came to me pretty quickly: the file could be written (initial chunk), but not modified (for the addition of subsequent chunks)! Adding Modify permissions for NETWORK SERVICE to RadUploadTemp cleared it up right away, as well as solving the file moving to TargetFolder on PostBack failure which I was experiencing on the live server. Hopefully this helps someone else! :)