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The activity and kinetics of delta 5-3 beta-dehydrogenase and 17 alpha-hydroxylase, using labeled pregnenolone as substrate, were measured in gonadal homogenates from rats fed alcohol or isocalorically substituted carbohydrate for 40 days. There was no difference in the rate or reaction kinetics for either enzyme noted between control and alcohol-treated animals when the assays were carried out in the presence of saturating amounts of exogenous pyridine nucleotide cofactors. However, when exogenous cofactors were omitted from the reaction mixture, there was decreased activity of the delta 5-3 beta-dehydrogenase system and increased activity of the 17 alpha-hydroxylase reaction. Furthermore, a cofactor-specific inhibiting effect on delta 5-3 beta-dehydrogenase activity by NADH and NADPH was found. Incubation of gonadal homogenates from the alcohol-treated animals with pyruvate on lactate (in the absence of exogenous cofactors) resulted in an increase and a decrease, respectively, in enzyme activity. These studies indicate that chronic alcohol use decreases gonadal delta 5-3 beta-dehydrogenase activity and that this is most likely due to an effect of the agent on the concentration and/or availability of pyridine nucleotide cofactors rather than to a direct effect on the enzyme. This phenomenon may account for the mechanism by which alcohol decreases testosterone secretion in these animals.