The enzymatic activity of renin is increased in plasma of patients with renal failure, possibly because of the deficiency of a renin inhibitor. Our study was undertaken to identify renin inhibitors and to compare their activities in plasma of 10 normal humans and 10 patients with renal failure. In vitro, both human renal renin and purified mouse submaxillary renin were inhibited by intact plasma and by a high molecular weight (greater than 65,000 daltons) and a lower molecular weight (55,000 daltons) plasma fraction (HMF and LMF, respectively) obtained by Sephadex chromatography. Most plasma proteins were recovered in HMF, and LMF also contained a small amount of protein; however, renin inhibition by HMF and LMF was not dependent on the presence of intact protein. HMF extracted from normal and uremic plasma inhibited renin to a comparable extent. However, LMF from uremic plasma inhibited renin to a lesser extent (p less than 0.01) than LMF from normal plasma. HMF-free plasma of normal subjects contained a specific renin-inhibiting neutral lipid component that was absent in uremic plasma. Thus, circulating renin inhibitors may contribute to the overall activity of the renin-angiotensin system, and increased enzymatic activity of renin in plasma of patients with renal failure may be related to the deficiency of a normally occurring neutral lipid renin inhibitor.