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This may occur for various reasons depending on the version of Exchange Server that you are running, but most typically for configuration changes that occur in IIS or in the permissions of the OWA directories.
I have found that a reapplication of the latest service pack usually corrects the problem, or sometimes even a simple reboot of Exchange Server. You can also check out Microsoft Knowledge Base article 298513, Removal of application mappings may cause an HTTP 404 error in Outlook Web Access -- although that is specific to Exchange 2000.
Do you have comments on this Ask the Expert Q&A? Let us know.
Related information from SearchExchange.com:
Tip: IIS 6 file corruption flaw impairs OWA
Tip: Troubleshooting IIS-related OWA problems
Reference Center: Internet Information Server (IIS) resources
Reference Center: Outlook Web Access tips and resources
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