To test the hypothesis that the progestogen medrogestone has no effect on changes in lipoprotein metabolism evoked by continuous estrogen replacement therapy, paying special attention to high-density lipoproteins (HDL). Open multicenter randomized comparative trial. Postmenopausal hysterectomized women aged 49 to 64 years. Continuous oral treatment with 0.625 mg daily of conjugated estrogens (CE) alone (n = 55) or CE plus 5 mg of the progestogen medrogestone orally during the last 12 days of each 28-day cycle (n = 59). At baseline and at cycles 3, 6, and 13 we measured the plasma levels of apolipoprotein (Apo) A1, cholesterol in total HDL and in its subfractions HDL2 and HDL3, using density gradient ultracentrifugation. High-density lipoprotein cholesterol increased from baseline at all assessments in both treatment groups, being significantly greater in the CE group (+15% at cycle 13) than in the CE and medrogestone group (+8%). However, HDL2-cholesterol increased in both treatment groups, but with no significant difference between the two groups. High-density lipoprotein 3 cholesterol increased only in the CE group (+7% at cycle 13); there was no significant change in HDL3-cholesterol in the CE and medrogestone group. Low-density lipoprotein (LDL) cholesterol decreased from baseline at all assessments in both treatment groups (-6% and -9%, respectively, at cycle 13). The change in very low-density (VLDL) lipoprotein cholesterol was not significant in either of the two groups. Medrogestone had no significant effects on the estrogen-induced increases in apo A-1 and triglycerides nor on the decreases in ApoB and LDL-cholesterol. Neither hormone significantly affected VLDL-cholesterol or Lp(a) levels. Medrogestone did not eliminate the increase in plasma HDL levels evoked by CE.