Background: Studies have shown that there is a high prevalence of depression in cancer patients. Women with breast cancer may have an even higher risk of depression particularly in a postmenopausal or estrogen deficiency state. A small number of randomized controlled trials have examined the efficacy of antidepressants compared to that of a placebo in cancer patients, but some results have been difficult to interpret due to a heterogeneous patient group. In the current investigation, we screened newly diagnosed early stage breast cancer patients for depressive symptoms prior to the initiation of adjuvant therapy and investigated whether the oral antidepressant fluoxetine affected depressive symptoms, completion of adjuvant treatment, and quality of life. Methods: Patients with newly diagnosed early stage breast cancer were screened for depressive symptoms prior to the initiation of adjuvant therapy. Patients with depressive symptoms were randomized to a daily oral fluoxetine or a placebo. Patients were then followed for 6 months and evaluated for quality of life, completion of adjuvant treatment, and depressive symptoms. Results: A high percentage of patients with newly diagnosed early stage breast cancer were found to have depressive symptoms prior to the initiation of adjuvant therapy. The use of fluoxetine for 6 months resulted in an improvement in quality of life, a higher completion of adjuvant treatment (chemotherapy, hormonal therapy, chemotherapy plus hormonal therapy), and a reduction in depressive symptoms compared to patients who received placebo. Conclusions: An antidepressant should be considered for early stage breast cancer patients with depressive symptoms who are receiving adjuvant treatment. © 2007 Springer Science+Business Media, LLC.