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Two prospective multicenter, double-blind, randomized, controlled trials were conducted to examine the safety and efficacy of three once-a-week continuous combined 17β-estradiol/levonorgestrel (E2/LNG) transdermal systems (E2 0.045 mg/day with 0.015, 0.030, and 0.040 mg/day LNG) for the treatment of vasomotor symptoms and prevention of estrogen-induced endometrial hyperplasia in healthy, postmenopausal women.In study 1, performed in 293 hysterectomized and nonhysterectomized women with moderate to severe hot flushes, transdermal E2/LNG (E2 0.045 mg/day with 0.030 and 0.040 mg/day LNG) was compared with placebo for three 28-day treatment cycles. The frequency and severity of hot flushes were recorded daily. In study 2, performed in 845 women with intact uteri, transdermal E2/LNG (E2 0.045 mg/day with 0.015, 0.030, and 0.040 mg/day LNG) was compared with transdermal E2 0.045 mg/day monotherapy for thirteen 28-day treatment cycles. Women with endometrial tissue sufficient for evaluation underwent endometrial biopsy assessment at the end of cycle 13. Bleeding patterns were assessed throughout the study, and the Women's Health Questionnaire was used to assess well-being.In study 1, transdermal E2/LNG (E2 0.045 mg/day with 0.030 and 0.040 mg/day LNG) significantly decreased the number and severity of hot flushes when compared with placebo. Symptom relief was seen as early as 2 weeks posttreatment. Similarly, in study 2, all three doses of transdermal E2/LNG and E2 controlled hot flushes with no differences between groups. In study 2, no women receiving transdermal E2/LNG developed endometrial hyperplasia compared with 19 (12.8%) who received transdermal E2 0.045 mg/day (p < 0.001 for each dose). Significant improvements from baseline in scores on the Women's Health Questionnaire for vasomotor symptoms, sleep problems, sexual function, cognitive difficulties, and total score were noted at all or most time points with both transdermal E2/LNG and E2. Application-site reactions, vaginal hemorrhage, and breast pain were the most common adverse events reported with transdermal E2/LNG. The proportion of women with amenorrhea increased over time in all treatment groups in study 2.All three doses of this once-a-week combined E2/LNG transdermal system rapidly and effectively control vasomotor symptoms in postmenopausal women while protecting against endometrial hyperplasia. Amelioration of vasomotor symptoms also is accompanied by improvements in aspects of subjective well-being. Once-a-week transdermal E2/LNG, therefore, offers an effective and convenient formulation, the dosing of which can be individualized according to the needs of each patient.