The Exchange Team posted a quick note yesterday addressing a compatibility issue between .NET framework 4.6.1 and Exchange. As of right now (Feb 2016) .NET 4.6.1 is not supported. Framework 4.6 is also unsupported.
The currently supported version for Exchange 2013 and 2016 is 4.5.2. Framework 4.5 can also be installed on Exchange 2010–although 2010 will only use the OS installed 3.5.
The urgency of this statement is that 4.6.1 is now being pushed as a recommended update in Windows Update.
As with any series of patching it is always critical to review all updates against the Exchange Supportability Matrix. If you want support from Microsoft you must be within the boundaries of that matrix
If you are using WSUS it is always a good idea to put Exchange in its own update group. If you don’t have a patch management system then keep your servers on notify and download. Whichever update method you use be sure to not blanket accept all updates.
Microsoft has identified one possible compatibility issue with 4.6.1, where a mailbox may be accidentally quarantined, its databases dismount, or, an unnecessary failover to another DAG member. More info can be found in this KB article.
If you have already installed 4.6.1 (or 4.6) Microsoft recommends you uninstall the update.
Below is the note from Microsoft on the supportability of 4.6.1.
As we have already stated in the Exchange Supportability Matrix, at this time, this version of .NET framework is not supported by Exchange. In fact, we know of some issues if it is installed.
We are working with the .NET team to ensure that Exchange customers have a smooth transition to .NET Framework 4.6.1, but in the meantime, delay this particular .NET update on your Exchange servers (information on how this can be accomplished can be found in the KB article 3133990, How to temporarily block the installation of the .NET Framework 4.6.1).Nino Bilic
Join the conversation on Twitter @SuperTekBoy.