Please check your installations web.config file for the following:
1. Inside <system.webServer> . . . . <handlers> . . . </handlers> the following node:
<add name="RSSHandler" path="RSS.aspx" verb="*" type="DotNetNuke.Services.Syndication.RssHandler, DotNetNuke" preCondition="integratedMode" />
2. Inside <system.Web> . . . <httpHandlers> . . . </httpHandlers> the following node:
<add verb="*" path="RSS.aspx" type="DotNetNuke.Services.Syndication.RssHandler, DotNetNuke" />
RSS.aspx does not actually exist as a file as its function is provided by the above referenced handlers. If you have recently upgraded the non-working site's application pool to ASP.Net 4.0 the problem may be that the first reference above is the following (note the difference in the preCondition attribute value):
<add name="RSSHandler" path="RSS.aspx" verb="*" type="DotNetNuke.Services.Syndication.RssHandler, DotNetNuke" preCondition="integratedMode,runtimeVersionv2.0" />
If that is the case, remove the above bold-faced text from ALL handler registrations within that same <Handlers> section.
If this does not solve the problem for you, please advise what version of DNN is installed, whether or not it is running under an ASP.Net 4.0 application pool and if possible what version of Windows/Windows server/IIS it is installed on.