Objectives To establish whether transdermal continuous hormone replacement therapy (HRT) with estrogen/progestogen provides adequate long-term endometrial protection in postmenopausal women over a period of 96 weeks.Methods This multicenter, randomized, open-label, parallel-group study evaluated the endometrial effects and overall safety and tolerability of a transdermal matrix patch delivering estradiol (E2) 50 mu g/day and norethisterone acetate (NETA) 140 mu g/day (Estalis((R)); patches applied twice weekly without intermediate breaks) and a once-daily oral comparator (Kliogest((R)); one tablet containing E2 2mg/NETA 1mg) in postmenopausal women. A total of 406 women with an intact uterus, aged 44-69 years, were randomized in the 48-week core phase of the study, and 239 continued into the 48-week extension phase. Subjects were randomized in the ratio 3:1 to transdermal or oral E2/NETA treatment.Results No cases of endometrial hyperplasia or endometrial cancer were reported with either treatment during the core or extension phase. Both treatments were generally well tolerated, with most adverse events (> 90%) being mild to moderate, although minor differences in the tolerability profile were observed between treatments.Conclusions Continuous combined transdermal HRT with E2/NETA shows no evidence of an increased endometrial hyperplasia or endometrial cancer risk over a 96-week period.