Activity of stimulatory GTP-binding regulatory protein (Gs) in human erythrocyte membranes was assessed by activation of adenylate cyclase in S49 murine lymphoma variant cells to elucidate a relationship to alcohol consumption. In apparently healthy subjects, alcohol consumption < 50 g ethanol per week did not alter the Gs activity, but it was significantly higher (14.3%, P < 0.05) in moderate drinkers (50-150 g/week) than non-drinkers. Then, the Gs activity declined with a further increase in alcohol consumption (150-550 g/week). Those subjects with drinking levels of > 50 g/week also showed significant increases in other alcohol-related markers, Na+, K(+)-ATPase and gamma-glutamyltransferase. The Gs activity was significantly low in alcoholics (a 34.9% reduction). No such reduction was noted in patients with other diseases. The results indicate that the Gs activity in erythrocyte membranes is an alcohol-related marker in humans. The variation of Gs activity is distinctive from those of other alcohol-related markers.