The aim of this study was to compare the effects of sequential combined transdermal and oral postmenopausal hormone replacement therapies on serum lipid-lipoprotein profiles risk markers for cardiovascular disease. A prospective randomize study was designed: Ninety-six healthy nonhysterectomised postmenopausal women were randomized to receive either transdermal continuous 17beta-estradiol, 0.05 mg/d (Estraderm TTS, Novartis, Basel, Switzerland), with transdermal sequential norethisterone acetate, 0.25 mg/d (Estragest TTS, Novartis, Basel, Switzerland), or oral continuous conjugated equine estrogens, 0.625 mg/d (Premarin 0.625 mg, Wyeth, Philadelphia, U.S.A.), with oral sequential medroxyprogesterone acetate, 10 mg/d (Farlutal 5 mg, Deva, Istanbul, Turkey). 84 women completed the trial, 42 in oral and 42 in the transdermal group. The serum levels of total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, apolipoproteins AI and apolipoproteins B at 6 months after starting treatment were compared with baseline values for both therapies. Both oral and transdermal therapies significantly reduced serum levels of total cholesterol (208-190 mg/dL and 216-199 mg/dL, respectively, p=0.0001) and LDL-cholesterol (128-112 mg/dL and 140-127 mg/dL, respectively, p=0.001). The serum levels of triglycerides did not show any significant change with oral therapy, whereas this lipid fell (128-101 mg/dL, p=0.0001) significantly with transdermal therapy. We found significant decrease in HDL-cholesterol with transdermal therapy while there was no significant change with oral therapy. Apolipoproteins AI, the major protein component of HDL2 subfraction, was increased by oral therapy and lowered by transdermal therapy. As a conclusion, we have found that serum total cholesterol and LDL-cholesterol were lowered by both therapies, with no significant differences between treatments, whereas there were significant differences between treatments according to effects on serum triglycerides and apolipoproteins AI.