We examined the influence on carbohydrate and lipoprotein metabolism of oral contraceptives (OCs) containing two new third-generation progestogens, desogestrel and gestodene. This was a prospective randomized study in which monophasic combinations of 20 micrograms ethinyl estradiol (E2) and 150 micrograms desogestrel or 30 micrograms ethinyl E2 plus 75 micrograms gestodene were administered to 15 and 19 healthy women, respectively. An oral glucose tolerance test including measurement of insulin response was performed before treatment and after 3, 6, and 12 months of treatment. We also determined fasting plasma concentrations of total cholesterol; high-density lipoprotein cholesterol, including the subfractions high-density lipoprotein2 cholesterol and high-density lipoprotein3 cholesterol; low-density lipoprotein cholesterol; very low-density lipoprotein cholesterol; and triglycerides. A transient deterioration of glucose tolerance was observed despite unchanged levels of insulin after treatment with both compounds for 3 months. In both groups plasma levels of triglycerides, very low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol increased significantly after 3 months. After 12 months, a significant increase in the high-density lipoprotein cholesterol/total cholesterol ratio was observed in the ethinyl E2-desogestrel group, and no persistent changes in low-density lipoprotein cholesterol could be demonstrated in any of the groups. Our results indicate that treatment with either compound for 12 months has no effect on carbohydrate or lipoprotein metabolism known to increase the risk of cardiovascular disease.