Block all unknown requests when the application is not running?

If I understood this option right, it offers great boot protection, but might bork the system if a key file can’t load during system startup. Please correct me if I got it wrong.

What about starting Windows in Safe Mode, and unticking this option, if trouble strikes? Is that a viable plan?

I tested this setting, and yes indeed, it blocked a couple scripts that usually run on my system at startup before Comodo protection kicks in. They are not essential processes, so the fact that they got delayed was not a problem.

Yes booting into safe mode helps when made a configuration mistake that messes up normal windows boot up. When booted into safe mode CIS protection is not active.