This work describes a study of the effects of combined oral contraceptives (OCs) on lipid biosynthesis in platelets of female rats and women. A highly significant hypercoagulability due solely to increased activity of platelet factor 3 can be observed in women using combined OCs. The phospholipidic nature of factor 3 has been demonstrated. Phospholipids are implicated in the aggregation of platelets because they are the essential constituents of the platelet membranes and the precursors of prostaglandins. Platelets actively synthesize their own lipids, and combined OCs modify serum lipid metabolism. In each experiment, a control group of rats weighing 180-200 g received .5 ml/g body weight of olive oil once daily for 4 days. 3 groups of experimental rats received .5 ml of olive oil containing 10 mcg of ethinyl estradiol (EE) and 250 mcg of lynestrenol or 10 mcg of EE alone or 250 mcg of lynestrenol alone per 100 g of body weight. The doses were the equivalent of 1/2 that required to block ovulation in adult female rats. Platelets were studied on the 5th day. In another experiment a group of rats was given a triple dose of EE and lynestrenol on the 1st study day. Platelets were studied on days 1, 3, 5, and 8. Lipid biosynthesis was studied by incorporation of carbon 14 labelled acetate and mevalonate precursors. Radioactivity was measured for the lipids as a whole and for different lipid fractions separated by chromatography. Incorporation of carbon 14 labelled acetate was augmented by 44.6% in animals receiving EE and lynestrenol and by 43% in animals receiving EE alone, but was not modified in animals receiving lynestrenol alone. In animals receiving a triple dose of hormones, incorporation was maximal on the 3rd day, diminished on the 5th day, and normal after 8 days. The EE component thus appears to be responsible for modifications in platelet lipid metabolism during OC use. The response appears after a latency period and seems to be irreversible, since the duration of life of platelets is 4-5 days. The increased synthesis occurs mainly in cholesterol and its precursors lanosterol and dihydrolanosterol. Supplemental in vitro experiments suggested that lanosterol was responsible for the increased platelet activity. 17 nonsmoking women aged 32 years on average who took no medications were compared to 18 women aged 30 years on average who took OCs with estrogen doses of 30-40 mcg for at least 6 months. As in the rat studies, lipid biosynthesis was analyzed by incorporation of carbon 14 labelled acetate or mevalonate in the platelets. Compared to control women, the women on OCs showed an augmentation of 37% in incorporation of mevalonate and 28% of acetate. The labelled acetate showed a higher incorporation at the level of each of the lipid fractions. Mevalonate showed the highest augmentation in the lanosterol fraction. 43% of the women taking OCs showed an increased platelet sensitivity to thrombine. The increased sensitivity was correlated with increased lanosterol synthesis, but the relation was only observed in women taking OCs. The phenomenon is of interest because of its possible relationship to the increased risk of thromboembolic accidents in women taking OCs.