OBJECTIVE Second malignant neoplasms (SMN) are devastating late complications of childhood acute lymphoblastic leukemia (ALL) and its treatment. We evaluated the incidence and type of SMN diagnosed before leukemic relapse in a large series of patients with ALL. METHODS We reviewed the outcome of all patients treated for childhood ALL between 1972 and 1995 on Dana-Farber Cancer Institute (DFCI) and DFCI ALL Consortium protocols. The follow-up time from diagnosis of ALL to induction failure, relapse, remission death, or SMN, whichever occurred first, ranged from 0 to 24.0 years (median, 7.6 years; mean, 6.7 years). RESULTS Thirteen SMNs were diagnosed among 1,597 patients. Eight tumors occurred in a radiation field (five in the CNS and three in the head and neck), two occurred outside of a radiation field (one adenocarcinoma of the sigmoid colon and one epithelioid sarcoma of the chest wall), and three were hematopoietic malignancies. The median time to occurrence was 6.7 years (range, 1.0 to 17.2 years) and the cumulative incidence of second malignancy before another first event was 2.7% (95% confidence interval, 0.7 to 4.7). The risk of a first event, which included induction failure, relapse, or remission death, was 31.0% (95% confidence interval, 28.5 to 33.5). CONCLUSIONS We found a more than 10-fold risk of other first events when compared with SMN. Thus, we conclude that SMN before first relapse is a relatively uncommon occurrence among survivors of childhood ALL. Future therapeutic regimens must focus on reducing leukemia relapse and enhancing quality of life, as well as preventing SMNs.