From May 1979 to March 1983, 76 evaluable patients with lymphoblastic lymphoma (LBL) were treated by members of the Pediatric Oncology Group (POG). Forty-six children treated by the six-drug A-COP+ regimen (Adriamycin [doxorubicin; Adria Laboratories, Columbus, OH], vincristine, prednisone, cyclophosphamide, methotrexate, and hydrocortisone) were compared in a prospective randomized trial with 30 patients receiving the modified ten-drug LSA2-L2 (cyclosphosphamide, vincristine, methotrexate, Daunomycin [daunorubicin cerubidine; Wyeth Laboratories, Philadelphia], prednisone, cytarabine, thioguanine, asparaginase, hydroxyurea, and carmustine) regimen. After adjusting for stage (I and II v III v IV), there was no statistically significant difference (P = .19) between A-COP+ and LSA2-L2 regimens on the basis of 3-year survival and disease-free survival (62% v 72% and 53% v 58%, respectively for the two treatment regimens) but the power of analysis and thus the ability to detect a clinically meaningful difference in the outcome with the two regimens was limited by the small number of patients. Neither therapy was effective for most patients with stage IV disease, with failure occurring in six of seven children receiving A-COP+ regimen and eight of 11 patients receiving LSA2-L2. Although the LSA2-L2 regimen was more toxic during the induction of remission, the toxicity during maintenance was acceptable and similar for both treatments. CNS relapse was not a significant problem whether cranial radiation with intrathecal (IT) therapy (A-COP+) or IT therapy alone (LSA2-L2) were used. Our results confirm the overall effectiveness of the LSA2-L2 regimen in children with LBLs, especially those initially free of bone marrow or CNS involvement, but were inconclusive as to the inferiority or superiority of this regimen over the A-COP+ regimen.