Twenty-three patients with oat cell cancer of the lung were randomized to receive chemotherapy with POCC (procarbazine, 100 mg/m2/day orally, Days 1-14; vincristine, 2 mg iv, Days 1 and 8; cyclophosphamide, 600 mg/m2 iv, Days 1 and 8; and CCNU, 60 mg/m2 orally, Day 1) or COM (cyclophosphamide, 2000 mg/m2 iv, Day 1; vincristine, 2 mg iv, Day 1; and methotrexate, 30 mg/m2 iv, Day 15). After two to three cycles of chemotherapy, all patients were to receive radiotherapy to initially involved sites and then have chemotherapy continued. Patients treated with POCC had a median survival of 14 months vs 10 months for those treated with COM (P = 0.055). Eight of 15 first sites of relapse were intrathoracic and five of these eight had received radiotherapy to that site. Six central nervous system (CNS) failures were evenly divided between the two chemotherapy programs. Thus, the CNS penetration of procarbazine and CCNU in the POCC combination did not prevent CNS relapse. All future patients will receive prophylactic brain radiotherapy.