Here's an interesting tidbit that I haven't seen mentioned elsewhere. In testing a ClickOnce application on a (virtual) machine without the .NET framework installed, I first tried to run the application by clicking the launch link (just like I think many users would). Much to my initial surprise, it popped up the dialog box to download the application file. I checked the server configuration, and everything looked okay, meaning the .application extension was associated with the correct MIME type (application/x-ms-application). After some reflection, I surmised this behavior was due to the fact that the .NET framework was not installed on the client machine. Once the framework was installed, the launch link did launch the application. So if your users cannot launch a ClickOnce application, it might be because the don't have the framework installed, not because of any server configuration.