Purpose: This Phase III study was performed to determine whether chemotherapy plus b.i.d. or q.d. radiotherapy (RT) resulted in superior survival for patients with Stage III non-small-cell lung cancer (NSCLC). Methods and Materials: Patients with Stage III NSCLC and an Eastern Cooperative Oncology Group performance status of ≤1 were randomized to receive either standard q.d. RT (60 Gy in 30 daily fractions) or split-course b.i.d. RT (30 Gy in 20 fractions b.i.d.) followed by a 2-week break and then 30 Gy in 20 fractions b.i.d. Both arms included etoposide and cisplatin (EP) during RT. Results: Between December 1994 and February 1999, 246 patients were accrued and 234 were deemed eligible and included in the analyses. Of the 234 patients, 123 had Stage IIIa disease and 111 had Stage IIIb disease. The incidence of severe (Grade 3 or greater) acute nonhematologic toxicity (q.d. RT, 53% vs. b.i.d. RT, 65%) and severe (Grade 3 or greater) hematologic toxicities (thrombocytopenia, 41% q.d. RT vs. 39% b.i.d. RT; neutropenia, 80% q.d. RT vs. 81% b.i.d. RT) was not significantly different between the treatment arms. Five patients (3 in q.d. RT group and 2 in b.i.d. RT group) died as a result of acute toxicity. The follow-up ranged from 2 to 73 months (median 43). No significant differences were found between the q.d. and b.i.d. RT arms in terms of time to progression (p = 0.9; median 9.4 and 9.6 months, respectively), overall survival (p = 0.4; median 14 and 15 months and 2-year survival rate 37% and 40%, respectively), and cumulative incidence of local failure (p = 0.6; 2-year rate 45% and 41%, respectively). Conclusion: This program of split-course b.i.d. RT plus EP was not superior to standard q.d. RT plus EP. The toxicity, tumor control, and survival rates were similar with either b.i.d. or q.d. RT. Our future efforts will concentrate on new combinations of systemic therapy and innovative methods of administering increasing doses of RT. © 2002 Elsevier Science Inc.