The aim of our study was to assess the effect of various regimens and doses of hormone therapy and tibolone on the Atherogenic Index of Plasma (AIP). A total of 519 postmenopausal women attending our menopause clinic were studied in a prospective design. Women with climacteric symptoms were randomly assigned to receive 1 of the following regimens: tibolone 2.5 mg, conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 5 mg (CEE/MPA), 17beta-estradiol 2 mg plus norethisterone acetate 1 mg (E2/NETA), or 17beta-estradiol 1 mg plus norethisterone acetate 0.5 mg (low E2/NETA). Serum parameters were assessed at baseline and after 6 months and included total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, apolipoprotein A1 and apolipoprotein B. The AIP was assessed as the log (triglycerides [mmol/L]/HDL-C [mmol/L]). CEE/MPA treatment associated with lower mean LDL-C but higher mean triglyceride levels (-15.5 mg/dL +/- 3.6, P = 0.0001; 12.6 mg/dL +/- 4.8, P = 0.01). Furthermore, CEE/MPA treatment resulted in higher AIP levels (0.073 +/- 0.021, P = 0.001). On the contrary, both E2/NETA regimens and tibolone associated with lower mean triglyceride and HDL-C levels (E2/NETA, triglycerides: -9.8 mg/dL +/- 5.0, P = 0.049; HDL-C: -4.9 mg/dL +/- 1.8, P = 0.01, low E2/NETA triglycerides: -12.5 mg/dL +/- 4.1, P = 0.003; HDL-C: -4.7 mg/dL +/- 1.3, P = 0.001; tibolone, triglycerides: -21.9 mg/dL +/- 2.7, P = 0.0001; HDL-C: -12.7 mg/dL +/- 1.1, P = 0.0001). None of the 3 regimens had any effect on AIP. The effect of a particular regimen of hormone therapy on the lipid-lipoprotein profile differs depending on the parameter assessed. The use of unified markers such as AIP will be helpful in evaluating the overall effect of lipid-lipoprotein modulation on the cardiovascular system. In fact, the concurrent assessment of the therapy effect on both LDL-C and AIP may be more dependable in evaluating the cardiovascular impact of a given regimen.