Study Objective: To compare the survival of patients with locally advanced non-small cell lung cancer treated with single-agent vindesine, thoracic radiotherapy, or both treatment modalities. Design: Randomized, prospective, phase III trial. Setting: Multi-institutional, university-based national cooperative oncology group. Patients: The study included 319 patients with locally advanced, unresectable non-small cell lung cancer who had no evidence of extrathoracic metastases. All patients were ambulatory and had measurable disease. Some patients could not have surgery because of coexisting medical conditions. Intervention: Patients were randomly assigned to receive vindesine, 3 mg/m2 boyd surface area weekly; standard thoracic radiotherapy, 60 Gy over 6 weeks; or both vindesine and thoracic radiotherapy. Vindesine was administered for 6 weeks and then every other week to patients who had no disease progression. Patients who developed progressive disease while receiving vindesine or radiotherapy alone were crossed over to radiotherapy or vindesine, respectively. Response assessment took place at week 6. Results: The overall response rate was superior in the radiotherapy arms (radiotherapy alone, 30%; radiotherapy plus vindesine, 34%; vindesine alone, 10%; P = 0.001). However, with a minimum follow-up of 42 months, no improvement in survival has been seen with radiotherapy. The medial survival was 8.6 months for patients receiving radiotherapy alone, 9.4 months for those receiving radiotherapy plus vindesine, and 10.1 months for those receiving vindesine (P = 0.58). Radiotherapy also failed to improve long-term survival. The 5-year survivals were 3%, 3%, and 1%, respectively (P = 0.56). Conclusion: Patients with non-small cell lung cancer who have inoperable, nonmetastatic disease gain no clinically meaningful survival adventage with immediate thoracic irradiation, even when modern megavoltage radiation therapy techniques and equipment are used.