To assess the importance of non-ADH ethanol metabolism, ADH-negative (ADH-) and ADH-positive (ADH+) deermice were fed for 2-4 weeks liquid diets containing ethanol or isocaloric carbohydrate. They consumed progressively increasing amounts of ethanol. Blood ethanol clearance (BEC) increased significantly in both strains. It remained almost unchanged at low ethanol concentrations (5-10 mM), but at high levels (40-70 mM) BEC was strikingly increased with significant differences between ethanol-fed and control animals. Kinetics were consistent with the activity of a non-ADH high Km system such as the microsomal ethanol-oxidizing system (MEOS). Naive ADH- had a more active MEOS and more abundant SER than naive ADH+. After ethanol feeding, MEOS was increased 3-4 times in both strains. There was striking proliferation of SER and cytochrome P-450 was enhanced significantly. Expressed per P-450, MEOS activity was higher in ADH- than ADH+. Thus despite absence of ADH, ADH- deermice can consume large amounts of ethanol: this is associated with increased BEC, SER proliferation, enhanced MEOS activity and quantitative and qualitative changes of cytochrome P-450.