Rationale: Interstitial lung disease (ILD) occurs in Japanese non-small-cell lung cancer (NSCLC) patients receiving gefitinib. Objective: To elucidate risk factors for ILD in Japanese NSCLC patients during treatment with gefitinib or chemotherapy. Methods: In a prospective epidemiological cohort, 3166 Japanese patients with advanced/recurrent NSCLC were followed for 12 weeks on 250 mg gefitinib (n=1872 treatment periods) or chemotherapy (n=2551). Patients who developed acute ILD (n=122) and randomly selected controls (n=574) entered a case-control study. Adjusted incidence rate ratios were estimated from case-control data by odds ratios (ORs) with 95% confidence intervals (CIs) using logistic regression. Crude (observed) incidence rates and risks were calculated from cohort data. Results: The observed (unadjusted) incidence rate over 12 weeks was 2.8 (95%CI 2.3-3.3) per 1000 person-weeks - 4.5 (3.5-5.4) for gefitinib vs. 1.7 (1.2-2.2) for chemotherapy. Adjusted for imbalances in risk factors between treatments, the overall OR for gefitinib vs. chemotherapy was 3.2 (1.9-5.4), elevated chiefly during the first 4 weeks (3.8 [1.9-7.7]). Other ILD risk factors in both groups included: older age; poor WHO performance status; smoking; recent NSCLC diagnosis; reduced normal lung on CT scan; pre-existing chronic ILD; concurrent cardiac disease. ILD-related deaths in patients with ILD were 31.6% (gefitinib) vs. 27.9% (chemotherapy); adjusted OR 1.05 (95%CI 0.3-3.2). Conclusions: ILD was relatively common in these Japanese NSCLC patients during therapy with gefitinib or chemotherapy, being higher in the older, smoking patient with pre-existing ILD or poor performance status. The risk of developing ILD was higher with gefitinib than chemotherapy, mainly in the first 4 weeks.