Interstitial lung disease associated with gefitinib is a critical adverse reaction. When geftinib was administered to EGFR-unknown patients, the interstitial lung disease incidence rate was approximately 3-4% in Japan, and usually occurs during the first 4 weeks of treatment. However, it has not been fully investigated in EGFR-mutated patients. We collected clinical records of participants of two Phase III trials (WJTOG 3405 and NEJ 002), which compared gefitinib with platinum doublet chemotherapy. All patients were EGFR mutated, chemo-naïve and had good performance status. A total of 402 patients were enrolled in this study. In the gefitinib arm, 10 (5.0%) of 201 patients developed interstitial lung disease, of whom five (2.5%) were Grade 3 or greater, with two deaths (1.0%). In contrast, only one patient developed interstitial lung disease (Grade 1) in the chemotherapy arm. With regard to gefitinib, smoking history was significantly associated with developing interstitial lung disease (odds ratio 0.18; 95% confidence interval: 0.05-0.74; P = 0.01). The cumulative incidence rate of interstitial lung disease was similar in the 0-4, 5-8 and 9-12 week time periods. However, between smokers and never-smokers, cumulative incidence rates in the first 4 weeks were significantly different (4.7% versus 0%, P = 0.03). Three of 10 patients developed interstitial lung disease after 8 weeks of gefitinib administration (days 135, 171 and 190, respectively). Among EGFR-mutated patients, the incidence of interstitial lung disease associated with gefitinib was not different from that in previous reports. Smoking history was associated with developing interstitial lung disease, and smokers had a higher incidence rate of interstitial lung disease in the first 4 weeks.