A well-regarded and easy-to-use cleaner is
PC Tools' Registry Mechanic which runs at bootup. I use it on all our computers. It is easy, safe, and runs by itself.
For a more thorough cleaning, we use
jv16 Power Tools, but this is more for someone who knows what they are doing.
Another simple-to-use and well-regarded Registry cleaner is part of
CCleaner, which we use daily to not to clean up the Registry but to clean out temporary Internet files, cookies, etc. CCleaner is free for personal use.