It's Not Worth The Risk
The registry is nothing but a glorified database. The operating system uses this database, but it does not use a linear search routine to access the database, so the size of the database, erroneous or unnecessary entries in the database, don't have any noticeable effect on the efficiency or performance of the operating system.
On my tower I have an installation that has been constantly upgraded from Windows 95 OSR2 to Windows 98 to Windows 2000 Pro to its current XP Pro, with never a clean install. I also have a customized parallel installation of XP on a second hard drive (both drives are Maxtor SATA) in this machine. The registry of the upgraded installation is over 3 (three) times the size of the registry of the customized version, but both installations have the same applications installed; the upgraded installation has had many, many applications uninstalled, with no doubt a great many useless and dead registry entries that were left behind. That installation is essentially 12+ years old (through many hardware upgrades, I might add).
I keep both installations current with Windows updates, AV updates, etc. Benchmark tests on the two installations (using exactly the same hardware) show no discernable difference in performance between the two; (the edge tips ever so slightly to the installation with the larger registry). Boot times are virtually identical.
My opinion is that registry cleaners are nothing but snake oil. There is no need to clean the registry. Any real errors on the registry will likely cause your PC to fail to boot. When that happens, use the boot options menu to boot to the last known good configuration. That is, more often than not, the only cleaning of the registry that you need.
If your PC is booting successfully, you don't need to clean the registry. If it is running too slowly to suit you, then you should get rid of unnecessary toolbars, weather on your desktop, download managers, update managers, speed launchers, etc. Empty your temporary internet files, empty your Temp folder, and defrag your drive(s).
So-called registry cleaners at best make no improvement in performance, and more often than not cause more harm than good, deleting "errors" that the operating system needs in order to run properly, and at worst can make a system unbootable. They are definitely not worth the risk.