Several investigations have suggested that disruption of circadian rhythms may provide the foundation for the development of mood disorders such as bipolar disorder (BP) and major depressive disorder (MDD). Recent animal studies reported that prokineticin 2 or prokineticin 2 receptor gene deficient mice showed disruptions in circadian and homeostatic regulation of sleep. This evidence indicates that prokineticin 2 gene (PROK2) and prokineticin 2 receptor gene (PROKR2) are good candidate genes for the pathogenesis of mood disorders. To evaluate the association between PROK2, PROKR2, and mood disorders, we conducted a case-control study of Japanese samples (151 bipolar patients, 319 major depressive disorder patients, and 340 controls) with four and five tagging SNPs in PROK2 or PROKR2, respectively, selected by HapMap database. We detected a significant association between PROKR2 and major depressive disorder and bipolar disorder in the Japanese population. In conclusion, our findings suggest that PROKR2 may play a role in the pathophysiology of mood disorders in the Japanese population. However, because our samples were small, it will be important to replicate and confirm these findings in other independent studies using larger samples.