I think there are two levels of registry cleaner.The first is the "hands off" variety which do the work for you and do not allow you to interact with them. The "hands off" variety is the safest to use as these utilities seldom if ever correct any but the most obvious errors in the registry. They do not require or allow for any further digging or analysis on the part of the user. This kind of utility scans,then displays the errors then fixes them, usually by simply deleting the invalid entries. Some of these utilities scan your C drive for corrections as they scan,some do not,at least not by default. Of these scanners I recommend Tweak Now RegCleaner and Registry Mechanic. Both are excellent entry level registry cleaners,especially TweakNow which has settings options for more advanced users.TweakNow is also free for non-commercial use.
The second level Registry cleaner allows for more comprehensive user adjusted scans. These utilities are potentially dangerous for all but the most advanced users. They require that the user be very familiar with Windows processes and registry. A greater degree of caution is required when selecting the "fix problems" options at the end of each scan.
Of these I have found System Mechanic's registry cleaner most problematic. It identifies entries that other reg utilities do not. I have found leaving these entries does not affect system performance. Half the time when you actually do select the "fix" option, a warning appears regarding deletion of the entry. I have checked the "help file " but found very little guidance as to which registry entries are safe to delete.
I much prefer Registry First Aid which allows for comprehensive scanning and provides many options for each entry or string found after each scan. From its interface you can select to go to the net to look up the entry or you may choose to go straight to the key in regedit. The corrections sometimes include rerouting the entry back to its parent application, a feature which I find logical and rare. I get best results running Registry First Aid in safe mode.
I also like its "leave entry without change" option which I find useful and most thoughtful on the part of the developer as not all inconsistent registry entries shoud be removed.