I’ve had this problem with R3 now its the same with R4.
Basically load up my custom UI in the startup folder. Restart zbrush and it asks me to activate?? Is this a known issue?
are you using a custom UI that you built before R4?
Yes, I think I made it in 3 R1. Though surely this is the whole point in saving out a custom UI?
it would be, but the way UI works changed…new buttons, etc, so your old UI doesn’t work anymore. Kinda sucks, but everyone in the office here had to remake their UI as well.
Yeah that really sucks! 
Sort it out pixologic! :\