Subfractions of high-density lipoprotein cholesterol and its apolipoproteins were followed up in 58 postmenopausal women during three cycles of unopposed estrogen replacement therapy with 2 mg of estradiol valerate daily. During the last 10 days of the following three cycles the women received sequential addition of either 250 micrograms of levonorgestrel, 10 mg of medroxyprogesterone acetate, or 200 mg of natural micronized progesterone. Both progestogens significantly decreased total high-density lipoprotein cholesterol as well as subfraction 2 of high-density lipoprotein. Data suggest that doses and relative biologic activity of 19-norsteroids and 17-hydroxyprogesterone derivatives are more important for their metabolic effects than are qualitative differences. Natural progesterone had no apparent influence on high-density lipoprotein cholesterol or its subfractions and may develop into an attractive alternative to synthetic progestogens.