Depression is not an uncommon complaint of women with breast cancer and is usually assumed to be related to the cancer diagnosis itself or its treatment. As part of a prospective clinical trial of adjuvant therapy of node negative breast cancer, 301 patients treated and assessed by one oncologist (SEJ) were serially questioned for symptoms of depression in the first 6-12 months after completing initial treatment (surgery, radiation therapy, and/or chemotherapy). Two hundred and fifty-seven patients were evaluable for assessment of depression; 155 were receiving tamoxifen and 102 were not. Twenty-six patients had symptoms of depression including 23 (15%) treated with tamoxifen compared to 3 (3%) in the group not placed on tamoxifen (p < 0.005). Of the 23 patients with depression in the tamoxifen group, symptoms were temporally related to the initiation of therapy and occurred generally in the first 2 months of treatment. Eight patients had mild symptoms not requiring a dose reduction, 8 had significant depression requiring a dose reduction to relieve symptoms, and 7 required discontinuation of tamoxifen. We conclude that clinical depression as a side effect of tamoxifen therapy may be more common than previously believed and should be further rigorously investigated to confirm or deny our clinical impressions.