That setting does not seem to matter. It was not set as the default program. But even after I set it as the default - this box continues to appear on program startup.

WIN10 does not show the Thunderbird Registry settings at all. MAILTO is set to Thunderbird URL.

I am the admin user on my machine already, fyi.

Why is it that all the Registry keys are not getting set up with the Thunderbird version? I do not find any of the keys mentioned above in the registry.

Is there any other solution to this issue?

I did uninstall and re-install Thunderbird as Administrator. Set Thunderbird as Default Mail client.

No change in behavior though.

Do not know why that option keeps coming up each time Thunderbird is started, and is really painful to see.

I'm using Win 7 & Thunderbird 45.5.1 solved problem by:

Tools/Options/System Intergration - "Always check if Thunderbird is default mail client on startup"..

It's unchecked, put a check mark on it & the that box will Not appear on start up... That's it... Revers Psychology ...

The fix going out in the next version. It might take 1-2 weeks to ship the new version 45.6.0