The effect of tolbutamide on renin secretion in rats was studied in vivo, and in vitro. Administration of tolbutamide in doses of 12.5 and 25 mg/kg body wt ip to two groups of rats produced no significant change in plasma renin activity compared to the control group. In the in vitro experiments renal cortical slices were incubated with increasing concentrations of tolbutamide (0--4 mg/ml). No significant increase in the net renin production was observed, whereas the concentration of cyclic AMP increased significantly in the incubation medium. These findings suggest that in the intact rats tolbutamide does not increase plasma renin activity. In the renal cortical experiments although tolbutamide increased cyclic AMP production, the increase may not have been sufficient to stimulate the net renin production. These results are of biological significance because of the possible effects of tolbutamide and increased plasma renin activity on the cardiovascular system.