Background. Although venlafaxine reduces self-reported hot flashes, no data have established the drug's impact on physiologically documented hot flashes. Two randomized, double-blind, placebo-controlled cross-over trials examined the efficacy of two doses of venlafaxine in relation to physiological and self-reported hot flashes and other outcomes, including negative affect, fatigue, sleep, and quality of life. Methods. Sample: 57 breast cancer survivors in the low-dose study; 20 in the high-dose study. Setting: university cancer clinics in the Southeast and Midwest. Intervention: 37.5 mg of venlafaxine (low-dose study) or 75 mg of venlafaxine (high-dose study). Measures: hot flash frequency (physiological monitor, diary, and event marker), hot flash severity (diary), hot flash bother (diary), and questionnaires for hot flash impact on daily life, negative affect, fatigue, sleep, and quality of life. Results. Subjective but not physiological hot flash measures showed placebo effects. Venlafaxine resulted in modest decreases in hot flashes, but only hot flash interference improved differentially at the higher dose. The timing of venlafaxine's effects on hot flashes varied by dose. Only women with a ≥50% decrease in physiological hot flashes experienced significant improvement in fatigue, sleep quality, and quality of life. Although side effects were mild, most patients discontinued venlafaxine long-term. Conclusions. Although venlafaxine resulted in modest and acute reductions in hot flashes with few side effects, it may not be tolerable to some patients long-term. At least 50% relief in physiological hot flashes may be needed for patients to demonstrate improvement in other outcomes, including decreased fatigue, improved sleep, and improved quality of life. ©AlphaMed Press.