OBJECTIVE The efficacy, bleeding patterns, and safety of continuous transdermal and sequential transdermal progestogen therapy were compared with those of oral progestogen therapy in postmenopausal women receiving transdermal estrogen. METHODS In an open-label, 1-year (13 treatment periods, 28 days each), randomized study, 774 postmenopausal women were assigned to receive 50 micrograms/day of continuous trans dermal estradiol with either continuous or sequential transdermal norethisterone acetate (NETA) in daily doses of 170 or 350 micrograms in a single transdermal patch or sequential oral progestogen (1 mg norethisterone [NET] or 20 mg dydrogesterone/day). RESULTS The average number of hot flushes/day decreased from prestudy by over 90% (P < .001), and this reduction was unaffected by different progestogen regimens. With sequential progestogen, bleeding incidence and the number of bleeding days did not change over the course of the study but were lower in the low-dose transdermal progestogen group. With continuous progestogen, the incidence of bleeding decreased in both the low- and high-dose groups, from 35% and 45% in treatment period 1 to 25% and 15%, respectively, at the end of treatment. Adverse event incidence was similar in all groups, with 23% to 36% of subjects reporting events possibly or probably related to HRT (excluding vaginal bleeding). Two cases of simple hyperplasia were reported (one in each low-dose progestogen group). Beneficial effects on coronary heart disease risk factors, such as reductions in total cholesterol and low-density lipoprotein cholesterol and increases in high-density lipoprotein-2 cholesterol levels, were measured in all treatment groups. Lipoprotein (a) was reduced in all but the oral progestogen group. CONCLUSIONS Continuous and sequential transdermal estrogen/progestogen treatments with estradiol/NETA appear to be effective and safe alternatives to continuous transdermal estrogen and oral sequential progestogen for the treatment of menopausal symptoms. Continuous transdermal therapy with estradiol/NETA may be more acceptable for a majority of patients, i.e., those who wish to avoid monthly bleeds, whereas the sequential regimen may be preferable when the clinician and/or patient believes monthly bleeding to be appropriate.