To clarify functional roles of histamine in the circadian clock system, circadian rhythms of behavior and clock gene expression in the brain were examined in the mouse lacking histidine decarboxylase (HDC-/- mouse). Wheel-running and spontaneous locomotion were recorded under light-dark cycle (LD) and constant darkness (DD). mPer1, mPer2 and mBMAL1 mRNA expression rhythms under LD and DD were measured in the suprachiasmatic nucleus (SCN), cerebral cortex and striatum by in situ hybridization. The activity levels under LD and DD in the HDC-/- mice were lower than that in the wild type regardless of activity types (wheel-running and spontaneous locomotion). The free-running period under DD was significantly longer in the HDC-/- mice than in the wild type. The 24-h profiles of mPer1, mPer2 and mBMAL1 mRNA expressions in the SCN were not different between the two genotypes. By contrast, the mPer1 and mPer2 mRNA rhythms in the other brain areas such as the cortex and striatum were significantly disrupted in the HDC-/- mice. These results suggest that histamine is involved in the circadian system especially in the output pathway or feedback route from behavior to the pacemaker in the SCN, and that mPer genes in the brain areas outside the SCN play an important role in the expression of behavioral rhythm.