The REGgamma proteasome has been reported as a shortcut to destruction of proteins. However, the physiological functions of REGgamma are largely unknown. To understand the potential biological roles of REGgamma associated with different tissues or cell types, we performed systematic analysis of REGgamma gene expression in 20 different tissues from mice, followed by validation of protein expression in mouse tissues and bioinformatic analysis of REGgamma gene expression profiles in selected human tissues. Comparative analysis of REGgamma distribution in different tissues from wild-type and REGgamma knockout mice indicates that REGgamma is present in many tissues and is specifically expressed in some cell types. The highest expression of REGgamma is in the testis and unique expression features of REGgamma are revealed in a subset of neurons, including retinal ganglion cells and Purkinje cells. It is also expressed in reproductive and gastro-intestinal organs. These expressed patterns suggest potentially important functions for REGgamma in the nervous system, reproductive system and in cells with proliferative capacity. Consistent with the importance of its expression in reproductive tissue, REGgamma deficiency results in dose-dependent reduction in litter size.