Perimenopause is often marked by vasomotor symptoms and dysphoria. Antidepressant studies have demonstrated decreased frequency and severity of hot flashes in breast cancer survivors and menopausal women. We hypothesized that venlafaxine would relieve both depressive and vasomotor symptoms in depressed perimenopausal women. Sixteen women fulfilling clinical criteria for climacteric phase and Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria for a depressive episode were enrolled in an open-label 8-week trial of extended-release venlafaxine. Depressive and climacteric symptoms were monitored using the Hamilton Rating Scales for Depression (Ham-D) and Anxiety (Ham-A), Clinical Global Impression (CGI) scale, and Greene Climacteric Scale (GCS). Serum follicular stimulating hormone (FSH) and estradiol concentrations were monitored. Significant decreases in Ham-D and Ham-A scores and the GCS psychiatric subscale were seen after 2 weeks of treatment. In an intention-to-treat analysis, 81% of the subjects demonstrated a therapeutic antidepressant response (>50% decline in Ham-D score) and 75% achieved clinical remission (Ham-D score < or =7) after 8 weeks of venlafaxine therapy (75-225 mg/day). Total GCS scores declined 60%, and GCS vasomotor subscores decreased among those with vasomotor symptoms at baseline. These data suggest that venlafaxine treatment improves overall well-being, reduces depressive symptoms, and may diminish baseline vasomotor symptoms in depressed perimenopausal women. Further studies are warranted to investigate the utility of venlafaxine in perimenopausal depression.