Since the liver is thought to be the major organ for the metabolism of renin, the rate-limiting enzyme in the renin-angiotensin cascade, we examined the kinetics and regulation of renin extraction by the isolated perfused rat liver. Partially purified, hog kidney renin was continuously infused into isolated rat livers perfused in a nonrecirculating manner with serum-free medium. Concentrations of renin in the portal and hepatic veins were measured by radioimmunoassay and first-pass hepatic extraction calculated. In livers from normal rats, steady-state, first-pass hepatic extraction of porcine renin ranged from 12.3 ± 0.9 to 25.5 ± 3.9% of the infused dose; at high renin infusion rates, hepatic extraction was saturable. Administration of captopril, a converting enzyme inhibitor, decreased hepatic extraction of renin by approximately 60%; enalaprilat, another converting enzyme inhibitor, had no effect. First-pass hepatic extraction of renin was also inhibited by the bile acid, taurocholate, in a dose-dependent manner. However, bilateral nephrectomy, which reduced endogenous plasma renin activity to unmeasurable levels, had no significant effect on hepatic extraction of renin by livers isolated from nephrectomized rats. These results demonstrate directly that the liver extracts renin in a dose-dependent and saturable manner, although the precise mechanism of uptake remains to be determined.