This 12-week, double-masked, double-dummy, randomized, parallel-group study compared the efficacy and safety of an estradiol matrix transdermal delivery system (Alora) in two strengths (50-microgram/d estradiol and 100-microgram/d estradiol) with placebo in postmenopausal women who were experiencing at least 60 moderate-to-severe hot flushes per week. In 273 postmenopausal women, the reduction in the frequency of moderate-to-severe hot flushes was significantly better than placebo within 2 weeks of initiating therapy in the 100-microgram/d group and within 3 weeks of initiating therapy in the 50-microgram/d group. The reduction in hot flushes for both active treatment groups remained significantly different from placebo throughout the 12-week trial. Improvement in vaginal cytology profile (maturation index) was observed in both active treatment groups. Serum estradiol concentrations were elevated to early-to mid-follicular levels, in proportion to dose, and the estradiol/estrone ratio remained within the expected premenopausal range. The incidence of estrogen-related side effects was modest but greater in the active treatment groups than in the placebo group: Breast pain was reported in 4.5% of the patients in the 50-microgram/d group, 5.3% of patients in the 100-microgram/d group, and none of the patients in the placebo group. Breakthrough bleeding occurred in 3.4% of women in the 50-microgram/d group, 20.2% of women in the 100-microgram/d group, and 4.4% of women in the placebo group. Only 3 (1.1%) patients terminated treatment because of skin reactions. This study demonstrates that this estradiol matrix transdermal delivery system is effective in the treatment of menopausal symptoms, while providing the skin tolerability desired by patients.