Estrogen therapy is the gold standard treatment for hot flashes and night sweats, but some women are unable or unwilling to use it because of associated risks. The serotonin-norepinephrine reuptake inhibitor venlafaxine hydrochloride is used widely as a nonhormonal treatment. While the clinical impression is that serotonin-norepinephrine reuptake inhibitors are less effective than estrogen, these medications have not been simultaneously evaluated in one clinical trial to date. To determine the efficacy and tolerability of low-dose oral 17?-estradiol and low-dose venlafaxine extended release in alleviating vasomotor symptoms (VMS). In total, 339 perimenopausal and postmenopausal women with at least 2 bothersome VMS per day (mean, 8.1 per day) were recruited from the community to MsFLASH (Menopause Strategies: Finding Lasting Answers for Symptoms and Health) clinical network sites between December 5, 2011, and October 15, 2012. Participants were randomized to double-blind treatment with low-dose oral 17?-estradiol (0.5 mg/d) (n?=?97), low-dose venlafaxine hydrochloride extended release (75 mg/d) (n?=?96), or placebo (n?=?146) for 8 weeks. The primary outcome was the mean daily frequency of VMS after 8 weeks of treatment. Secondary outcomes were VMS severity, bother, and interference with daily life. Intent-to-treat analyses compared the change in VMS frequency between each active intervention and placebo and between the 2 active treatments. Compared with baseline, the mean VMS frequency at week 8 decreased to 3.9 (95% CI, 2.9-4.9) VMS per day (52.9% reduction) in the estradiol group, to 4.4 (95% CI, 3.5-5.3) VMS per day (47.6% reduction) in the venlafaxine group, and to 5.5 (95% CI, 4.7-6.3) VMS per day (28.6% reduction) in the placebo group. Estradiol reduced the frequency of symptoms by 2.3 more per day than placebo (P?.001), and venlafaxine reduced the frequency of symptoms by 1.8 more per day than placebo (P?=?.005). The results were consistent for VMS severity, bother, and interference. Low-dose estradiol reduced the frequency of symptoms by 0.6 more per day than venlafaxine (P?=?.09). Treatment satisfaction was highest (70.3%) for estradiol (P?.001 vs placebo), lowest (38.4%) for placebo, and intermediate (51.1%) for venlafaxine (P?=?.06 vs placebo). Both interventions were well tolerated. Low-dose oral estradiol and venlafaxine are effective treatments for VMS in women during midlife. While the efficacy of low-dose estradiol may be slightly superior to that of venlafaxine, the difference is small and of uncertain clinical relevance. clinicaltrials.gov Identifier: NCT01418209.