The SAFEST registry cleaner I've found is Ace Utilities (which has many other useful utility functions). In default mode, it uses a time-tested list of critical registry entries that are excluded from automatic removal - so you can't easily cripple your system functions. You can select 'expert' mode for deeper scanning - but you'd better know what you're doing. If you do screw up by deleting a critical registry entry, a 'restore' button will reverse your action.
My next favorite would JV16 Power Tools, which also has other useful utility functions. It has an easy registry-search function - something Ace Utilities does not. With default settings, be careful about just accepting all registry-clean items - it can delete critical registry items.
Hope this helps!