Bupropion is commonly used in the treatment of nicotine dependence and depression, and in most people, does not cause sexual dysfunction, weight gain, or sedation. Given its attractive side effect profile, the efficacy of other newer antidepressants against hot flashes and anecdotal observations of resolution of hot flashes in some patients taking bupropion for nicotine dependence, it was decided to explore its clinical activity as a hot flash remedy in a pilot study. Between January 1999 and October 2004, 21 patients (7 men and 14 women) were enrolled in the study. Self-completed daily hot flash diaries were used to document the frequency and severity of hot flashes at baseline (week 1) and during the treatment period (weeks 2 through 5). Participants received bupropion 150 mg every morning for the first 3 days and then 150 mg twice per day for a total of 4 weeks. One woman did not provide any hot flash information and was excluded from the analysis. Five women could not complete the study because of side effects. The study did not show a reduction in hot flash frequency and/or severity significantly higher than what would be expected with a placebo. Even though the sample size was small, these results are consistent with bupropion's mechanism of action (norepinephrine reuptake inhibition without serotonergic effects) and what it is now hypothesized about the pathophysiology of hot flashes (increased noradrenergic activity and decreased serotonergic activity). These data suggest that bupropion should not be further investigated as a remedy for hot flashes.