Smoking markedly intensifies the risk of cardiovascular disease in women who use oral contraceptives. The mechanism of this effect is not known, but evidence in vitro and in male smokers suggests that nicotine and cigarette smoke can alter prostaglandin formation and platelet function. However, these effects had not been studied with regard to women. We evaluated the effects of smoking on prostacyclin formation and platelet aggregation in 38 women who were matched according to age and weight. These included 24 women who used oral contraceptives (15 smokers, 9 nonsmokers) and 7 smokers who did not use oral contraceptives. In addition, a control group comprised seven healthy, nonsmoking women who did not take oral contraceptives. Prostacyclin formation, reflected by the excretion rate of its stable metabolite 6-keto-prostaglandin F1 alpha, was measured by means of radioimmunoassay in 4-hour urine specimens obtained during a smoking-free period and after participants had inhaled smoke from four high-nicotine cigarettes. In addition, ex vivo platelet aggregation in response to adenosine diphosphate and the stable thromboxane/endoperoxide analog U 46619 was evaluated before and after the inhalation of cigarette smoke. Oral contraceptive users who smoked greater than or equal to 5 years had a lower basal 6-keto-prostaglandin F1 alpha level than nonsmokers or those with a smoking history of less than 5 years (84 +/- 11 versus 159 +/- 28 versus 171 +/- 18 ng/gm of creatinine, p less than 0.01). Inhalation of smoke from four high-nicotine cigarettes did not alter 6-keto-prostaglandin F1 alpha in the smokers who did not use oral contraceptives. However, excretion of 6-keto-prostaglandin F1 alpha was further reduced in the smokers who used oral contraceptives (133 +/- 20 to 86 +/- 9 ng/gm of creatinine, p less than 0.05). Platelet aggregation did not change after inhalation of cigarette smoke in the women who did not take oral contraceptives, but aggregation increased in participants who used oral contraceptives. These results suggest that prostacyclin inhibition may be an important mechanism for the increased cardiovascular risk in women smokers who take oral contraceptives.