In a prospective, nonrandomized study, the response of brain metastases (BM) from breast cancer to a standard systemic chemotherapy regimen was measured by clinical follow-up and serial computed tomography (CT) scans. Treatment consisted of 4-week courses of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in 20 patients or 3-week courses of cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF) in 2 patients. Seven patients had previously received CMF or CAF as adjuvant treatment or for progressive systemic disease. Another seven patients had been previously treated for BM with the use of surgery and/or radiation therapy (RT). Based on the results of clinical follow-up and CT scan, a response that lasted at least 6 weeks was seen in 13 patients (59%; 95% confidence interval, 37% to 80%), including 4 of the 7 patients with recurrent BM. Objective tumor regression occurred after two courses of chemotherapy in 76% of the patients who could be examined and after six courses in 47%. The median duration of neurologic remission in the 13 patients was 30 weeks (range, 15 to 66 weeks). The median overall survival time was 25 weeks (range, 2 to 83 weeks). The response rate of systemic disease paralleled the neurologic response. When compared with a matched group of historical control subjects treated with RT alone, chemotherapy induced a higher rate of neurologic response and led to a longer survival time. These results warrant further studies on the use of chemotherapy in BM from breast cancer.