Progesterone (P) is a mineralocorticoid (MC)-antagonist in vitro. During pregnancy, plasma P concentrations exceed aldosterone concentrations at least 50-fold, but plasma aldosterone increases only 4–8-fold in a compensatory manner. Since the in vivo anti-MC activity of P seems to be only moderate, we hypothesized that P is metabolized by enzymes of MC target tissue similar to the way cortisol is metabolized by 11β-hydroxysteroid dehydrogenase (11β-HSD) type 2 in order to protect the MC receptor. We, therefore, examined P metabolism using 4- 14 C-P in subcellular fractions of human postmenopausal and male kidneys, and in homogenates of one premenopausal kidney. We found that P is converted effectively, even at high P concentrations (10 −6 mol/l), to various metabolites: 20α-dihydro(DH)-P; 17α-OH-P; 17α-OH,20α-DH-P; 5α-DH-P; 3β,5α-tetrahydro(TH)-P; and 20α-DH,5α-DH-P. Homogenates of premenopausal kidney also showed conversion to 3α- and 5β-reduced P metabolites. These results confirm the existence of an efficient renal enzyme system as a possible mechanism of an enzyme-mediated MC receptor selectivity.