The aim was to investigate the contribution of the kidneys and the extrarenal tissues to the concentration of inactive renin in the circulation. Renin was determined in plasma from normal, conscious, male mice in strains with low (BALB/c) and high (Theiller) renin content in the submandibular glands. In untreated, conscious males, inactive and active renin concentration in plasma was 24.9 GU/I (range 13.6–40.1 GU/I) and 4.2 GU/I (0.6–8.8 GU/I), respectively in the BALB/c strain (n = 28). These values were not significantly different from the concentrations of inactive (29.2 GU/I, range 15.6–88.3 GU/I) and active (5.1 GU/I, range 1.9–10.4 GU/I) renin in Theiller's strain (n = 10). Thus, inactive renin comprised 80–90% of the total renin in plasma from normal, conscious, male mice of both strains. The percentage of inactive renin was similar to that found in humans. Following sialoadenectomy and bilateral nephrectomy, the plasma concentration of inactive renin was unchanged.The effect ofin vivoinhibition of the protein synthesis by intraperitoneal injection of emetine was also investigated. After 6 h of inhibition, inactive renin in plasma declined from 21.0 to 9.9 GU/I in normal mice. In contrast, inactive renin was unchanged in sialo-adenectomized and nephrectomized mice (29.1 versus 28.6 GU/I).Our findings suggest that the kidneys are the main source of inactive renin in the circulation. The data also indicate that the kidneys simultaneously secrete and remove inactive renin from the blood at approximately the same rate. The results do not lend support to the concept of activation of inactive renin in the blood, nor to the postulated substantial uptake of inactive renin by extrarenal tissues.