Hi smcartor,
Did you mean only one specific site collection have this issue randomly in you SharePoint environment? Multiple SharePoint front end servers?
Have you checked other site collections on these machines where the issue was replicated?
Please check if this issue can be replicated on other browsers like Firefox/Chrome.
Please try adding the SharePoint site url to IE browser "Local intranet" zone per the following article on multiple machines (if not work, also try adding url to Trusted sites zone), then test again.
http://mcgeeky.blogspot.in/2010/02/your-client-does-not-support-opening.html
Thanks,
Daniel Yang
Forum Support
If you have feedback for TechNet Subscriber Support, contact tnmff@microsoft.com.
Daniel Yang
TechNet Community Support
