Abrupt onset of hot flashes poses a significant problem for women treated with chemotherapy for breast cancer. Alternatives to hormone replacement, such as the use of the selective serotonin re-uptake inhibitor (SSRI) paroxetine hydrochloride, are being explored as therapies for hot flashes in this patient population. The present study investigated the efficacy of paroxetine for the treatment of hot flashes and associated symptoms in women with breast cancer. This study included 13 patients who were seen in the Psychosocial Clinic at Moffitt Cancer Center. They were referred by their medical oncologist after reporting complaints of significant difficulty with hot flashes. Baseline questionnaires were completed and a structured diagnostic interview for clinical depression was conducted, all of which were repeated 5 weeks after the paroxetine 20 mg daily was started. Significant improvements were seen in the ratings of hot flash severity (P = 0.002). In addition, significant improvements were observed in general, emotional, and mental fatigue. Rates of clinically significant depressive symptomatology also decreased and sleep quality improved significantly as well. Finally, the incidence of clinical depression improved from 39% at baseline to 8% after treatment. These preliminary data suggest that the antidepressant paroxetine can be helpful in the treatment of hot flashes and associated fatigue, sleep disturbance, and depression in women with breast cancer treated with chemotherapy. Further controlled studies are needed to more fully evaluate the efficacy of the SSRIs for hot flashes in women with breast cancer.