>Just thinking that if, for instance, the session uses a resource in a shared or readonly mode then it would work fine with other concurrent sessions but if the application at startup required exclusive or write access to that resource it might be a problem.

None of that applies, but, on the first hit to the site, the application object is initialized and accessible from every hit following that. I open a SQL Server connection at every hit so it is independant from other hits.

>I was thinking about errors that might occur and be untrapped in the Global.asax Application_Start() code. Do you have code in the Application_Error() handler that would let you know if an error occurred there ?

No error is logged.

>You probably need to narrow this problem down to more specific scenarios. For example see if replacing the DLL *always" works when there are *no* active sessions. And again, from a problem solving POV, 'a very long time' and 'not at all' at two very different things.....
>Could you put some logging code at various stages of the startup to give some indication of how far the process gets (maybe adding timing info so that if the application does eventually start you will have a better idea of where the delay occurs).....

This is very difficult to establish but I would think about it.