The optimal integration of radiation and chemotherapy for limited-stage small-cell lung cancer (SCLC) remains unclear. This phase III trial was conducted to determine whether chemotherapy plus interdigitating split-course thoracic radiation therapy (RT) improved survival compared with standard-dose continuous thoracic RT. One hundred fourteen patients were randomized to receive 50 Gy thoracic RT delivered in 2.0-Gy fractions given continuously (5 weeks) concurrent with the first 2 cycles of chemotherapy (arm A) or 50 Gy delivered via an interdigitating split course in 2.5-Gy fractions (8 weeks) concurrent with the first 3 cycles of chemotherapy (arm B). During the split-course RT, once-daily radiation was delivered on days 8-17 of each of the first two 21-day cycles and days 8-11 of the third 21-day cycle. All patients received the following chemotherapy: cisplatin/etoposide on cycles 1, 2, and 5 and cyclophosphamide/vincristine/doxorubicin on cycles 3, 4, and 6. Prophylactic cranial irradiation was recommended after a complete response to all therapy. One hundred ten eligible patients were randomized. Grade 3/4 esophagitis was reported in 9% of patients receiving continuous thoracic RT versus 4% of patients receiving split-course RT. Grade 3/4 hematologic toxicity was common in both treatment arms. Complete/partial response was observed in 80% of patients on arm A versus 84% on arm B. Overall survival rates at 5 years were 18% and 17% for arms A and B, respectively. Interdigitating split-course thoracic RT delivered in 2.5-Gy fractions was tolerable in patients with limited-stage SCLC but did not provide a survival advantage.