The influence of the anticarcinogen dehydroepiandrosterone (DHEA) on the metabolism and macromolecular interactions of the potent hepatocarcinogen dimethylnitrosamine (NDMA) was investigated. Male Sprague‐Dawley rats (2–3 mo old) were fed DHEA for 14 d at a dietary level of 0.8%. Compared with pair‐fed controls, the liver weights of the DHEA‐treated animals increased significantly (11.7 vs. 7.1 g) with increases, per total liver, in proteins including those of cytosol and microsomes as well as cytochromes P‐450 andb5. DNA content of the liver, however, remained constant. Five hours after a single ip dose of [14C]NDMA (30 mg/kg body wt, 42 μCi/rat) DNA methylation was reduced in the DHEA‐fed animals as measured by 7‐methyl‐ andO6‐methylguanine per mole of guanine, by 39 and 31%, respectively. The rate of NDMA metabolism was slightly higher in the DHEA‐fed rats as determined in vivo by the exhalation of14CO2and by the declining concentrations of NDMA in the blood. The incorporation of radioactivity from [14C]NDMA into hepatic proteins in vivo was greater (2.1‐fold) in the DHEA‐fed rats.