The effect of calcitonin (CT) on Ca-ATPase activity in the plasma membrane fraction of rat liver was investigated. CT (80 MRC [Metabolic Research Council] mU[units]/100 g BW [body wt]) administered s.c. to rats, caused a significant decrease in serum Ca, while increasing liver Ca. The administration of CT produced a rapid decrease of Ca-ATPase activity in the plasma membrane fraction of liver, whereas CT did not cause a significant alteration of p-nitrophenyl phosphatase activity. The maximal response of CT was obtained with 80 MRC mU/100 g BW. Meanwhile, the administration of imidazole (30 mg/100 g BW) which has a hypocalcemic effect, like CT, produced a significant increase in liver Ca and a corresponding fall in Ca-ATPase activity of the plasma membrane fraction. The reduction of Ca-ATPase activity produced by imidazole was significantly potentiated by the simultaneous administration of CT, and the rise in liver Ca was enhanced slightly. The action of CT on liver Ca may involve the decrease of Ca-ATPase activity in the plasma membrane of rat liver.