Women (27) with primary carcinoma of the breast with .gtoreq. 4 metastatic axillary nodes received prophylactic radiotherapy in addition to adjuvant vincristine, prednisone, cyclophosphamide, methotrexate and fluorouracil chemotherapy. When compared with 73 women who received chemotherapy alone, the relapse rate per month for the patients with radiation therapy was 4-fold greater, P = < 0.0001. Recurrence of 17 of 27 contrasts with relapse in 13 of 73 patients who did not undergo irradiation. By 8 yr, 14 of 27 patients who received radiotherapy had died, contrasted with 9 of 73 who received chemotherapy alone. The results for the irradiated subset were due to patient selection nor to shortening or underdosing of chemotherapy. Immunosuppression from radiation and systematic delay in initiating chemotherapy remain among the possible explanations. These data support the use of adjuvant chemotherapy and argue against the prophylactic use of radiotherapy following mastectomy for carcinoma of the breast.