Tamoxifen is a first-generation selective estrogen-receptor modulator that has been shown to decrease recurrence and prolong survival among premenopausal women with breast cancer; however, it also results in estrogen-insufficiency symptoms, the most common being hot flushes.The authors present a case in which tamoxifen apparently produced acute depression symptoms in a 34-year-old breast cancer patient.After two aborted periods of tamoxifen treatment, the patient was started on venlafaxine as a preventive measure before tamoxifen treatment was begun again.After 2 months of treatment with venlafaxine, tamoxifen was initiated for a third time, with no recurrence of her previous mood symptoms.Treatment of depression may result in better compliance with tamoxifen regimens and, thus, more favorable outcomes.