Between 1974 and 1982, 797 patients who had operable breast cancer were treated at the University of Texas M.D. Anderson Hospital and Tumor Institute at Houston with three adjuvant chemotherapy trials consisting of fluorouracil, doxorubicin, and cyclophosphamide (FAC). The incidence of second primary malignant tumors in this group of patients was evaluated and compared with that in a historical control group of patients who had stages II and III disease (n = 186) and who did not receive adjuvant chemotherapy following surgery. Radiotherapy was given to 54% (n = 433) of the chemotherapy-treated patients and to 96% (n = 178) of the controls. The median age of the patients was 49.6 and 55 years for the treated and control groups, respectively. Second neoplasms developed in 10 chemotherapy-treated patients and in nine control patients; rates at 5 years from initiation of therapy based on actuarial curves were 1.9 and 5.0%, respectively. These second tumors developed after a median latency period of 17.5 months for the FAC-treated group and 13 months for the controls. Two cases of leukemia developed in each of the two treatment groups. The rate of second malignancy in the chemotherapy-treated patients was not increased compared with that in the historical controls.