Serotonin-norepinephrine reuptake inhibitors are understood to be less effective than estrogen in treating hot flashes and night sweats, but these medications have not been simultaneously evaluated in one clinical trial to date. Joffe and coauthors conducted a 3-arm, 8-week randomized clinical trial comparing the efficacy of first-line low-dose hormonal therapy (estradiol, 0.5-mg/d orally) and a serotonin-norepinephrine reuptake inhibitor agent (venlafaxine extended release, 75 mg/d) against placebo for the treatment of vasomotor symptoms (VMS) in 339 perimenopausal and postmenopausal women. Compared with baseline, mean VMS frequency decreased by 53% with estradiol, 48% with venlafaxine, and 29% with placebo. Estradiol reduced VMS by 2.3 (95% CI, 3.1-4.7) more per day than placebo (P < .001), and venlafaxine by 1.8 (95% CI, 0.8-2.7) more per day than placebo (P = .005). No baseline demographic, menopause, or symptom profile characteristic predicted differential response to estradiol or venlafaxine.