OBJECTIVE: To evaluate the efficacy and tolerability of two doses of gefitinib in patients with relapsed progressive non-small cell lung cancer. PATIENTS AND METHODS: A randomized, double-blind, parallel, multicenter phase II study. 210 patients with progressive NSCLC who had received 1 or 2 prior chemotherapies (≥1 platinum-containing regimen) were randomized to receive 250 mg/d or 500 mg/d gefitinib. RESULTS: The efficacy of the 250 mg/d and 500 mg/d groups was similar. Objective remission rates were 18.4% (95% CI, 11.5-27.3) and 19.0% (95% CI, 12.1-27.9), respectively; among evaluable patients, symptom remission rates were 40.3% (95% CI, 28.5-53.0) and 37.0% (95% CI, 26.0-49.1), respectively; and median progression-free survival was 2.7 and 2.8 months, respectively; median overall survival was 7.6 and 8.0 months, respectively. Symptom remission rates were 69.2% (250 mg/d) and 85.7% (500 mg/d) for patients in tumor remission. Adverse reactions were mild (degree 1/2) at both dose levels and were mainly skin reactions and diarrhea. Drug-related toxicity was more common in the higher dose group. The percentage of patients who withdrew due to drug-related AEs was 1.9% (250 mg/d) and 9.4% (500 mg/d), respectively. CONCLUSION: Gefitinib second- and third-line treatment of advanced NSCLC has good antitumor activity and relieves patients’ symptoms. The dose of gefitinib 250 mg/d was better tolerated. Gefitinib 250 mg/d is an important and novel treatment option for patients with relapsed progressive NSCLC.