Oral contraceptives containing DL-norgestrel or norethindrone with ethinyl estradiol were administered by random assignment to 21 menstruating women, matched for anthropometric measurements, age, diet, alcohol consumption, smoking, and exercise habits. Pretreatment and 7-week treatment blood samples were obtained and assayed for serum cholesterol, triglyceride high-density lipoprotein cholesterol (HDL-C), and total high-density lipoprotein (HDL), HDL2a, HDL2b, and HDL3 subclasses by analytic ultracentrifugation. Subjects using the norethindrone oral contraceptive had a significant increase in HDL-C: baseline, 46 mg/dl; 7 weeks, 51 mg/dl. Values for the subjects using the norgestrel oral contraceptive were not significantly changed: 46 and 44 mg/dl, respectively. Users of the norethindrone oral contraceptive had significant elevations of total HDL and HDL3, while norgestrel oral contraceptive users demonstrated no significant changes. HDL2b increased with the norethindrone oral contraceptive and declined with the norgestrel oral contraceptive. The changes in HDL2b from baseline to treatment were not significant (p greater than 0.05), but the change with the norethindrone oral contraceptive did differ significantly from that with the norgestrel oral contraceptive (p less than 0.02). These changes may indicate oral contraceptive-induced alterations in HDL structure and metabolism that could be related to the risk of development of atherosclerosis.