In recent years, relationships of dehydroepiandrosterone and its sulfate ester dehydroepiandrosterone sulfate (DHEAS) with decreased risks of cardiovascular disease as well as a possible role in the aging process have been postulated. To explore the effects of cigarette smoking, a risk factor for cardiovascular disease, as well as age, on the levels of these adrenal androgens, we measured plasma levels of DHEAS in 543 healthy male subjects from the Physicians' Health Study. Blood specimens were collected between August 1982 and December 1984 and stored at -80 C. The overall mean DHEAS level was 3.47 mumol/L (+/- 2.12 SD). DHEAS levels were positively correlated with smoking habits (r = +0.16, P = 0.0002); current smokers had the highest age-adjusted DHEAS concentrations (4.27 mumol/L, P = 0.0005 compared with never smokers), followed by past smokers (3.47 mumol/L, P = 0.02) and never smokers (3.10 mumol/L). A marked linear decline of levels with age was observed, with an average decrease of 3% per year. These data suggest a moderate direct association with cigarette smoking and a powerful influence of age on decreasing levels of DHEAS. After adjusting for age and smoking habits, DHEAS concentrations were also inversely correlated with reported use of multivitamins (r = -0.16, P = 0.0002) and positively correlated with plasma retinol levels (r = 0.14, P = 0.002).