For those of you looking for a quick answer, it’s no. At least not as part of regular maintenance.
There has been a myth that registry optimization improves the performance of PCs for a long time. Back in the Windows 9x days, there may have been some merit to this. Microsoft even published a Registry Cleaner. But those days are well behind us (if you are still using Windows 95/98, I strongly recommend a new computer) and the resources in newer computers are such that cleaning the registry regularly is going to make no difference. A good analogy that I’ve seen is that registry cleaners are like sweeping out a single parking space in a parking lot the size of Montana.
More than being uneffective, registry cleaners have the potential to harm your computer. A registry cleaner that identifies the wrong key as being unecessary could have drastic effects on individual programs or even the Operating System itself.
That’s not to say that registry cleaners don’t have their place. A good registry cleaner such as CCleaner can resolve a variety of issues when used appropriately. The key is to only use them when resolving a specific issue, not to use them indiscriminately.
For those of you that support the use of registry cleaners as a part of regular maintenance, you have the chance to change my mind. All I need is hard data. Not a statement that your computer runs faster, but actual numbers, benchmarks, etc. If anyone has data that shows that regular use of registry cleaners improves performance in any significant way, please leave a link to said data in the comments. I have yet to come across anything like this.