NT's registry is implemented as a database. It shares many of the characteristics including fragmentation as items are added, removed, or changed. In particular, when items are removed from the registry, there is no cleanup mechanism to recover the now unused space in the database. Microsoft released RegClean to clean up some of the debris. Russinovich has released PageDefrag which can defrag the page file and registry hive files.
Fragmentation can become significant over time on a busy system.
Use either tool with caution. There is no tool to compress the registry, to recover lost space and reindex the fundamental database. But there is a method to achieve this result. Backup the registry and be prepared to get back to where you started if things go wrong. The repair version of the hives is compressed and reorganized.