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Background Compared with cytotoxic chemotherapy, the efficacy and safety of immune checkpoint inhibitors (ICIs) for patients with interstitial lung disease and non-small cell lung cancer (ILD-NSCLC) are unclear.Methods Data of patients in a Japanese nationwide insurance claims database with ILD-NSCLC who received ICIs (ICI group, n=1748) and those who received only chemotherapy without ICIs (chemotherapy group, n=6362) were extracted. Landmark analyses were performed to compare overall survival (OS) between the two groups. Propensity-score matching was performed to compare 753 patients who received ICI as the first-line treatment (first-ICI group) and 753 from the chemotherapy group with matched backgrounds (matched chemotherapy group).Results The ICI group had a significantly longer median OS of 19.7 months than the chemotherapy group (9.9 months; HR 0.51, 95% CI 0.47 to 0.54, p<0.001). In landmark analyses at 3, 6, 9 and 12 months, the ICI group had a significantly longer OS than the chemotherapy group (all p<0.001). The incidence of drug-induced ILD (DIILD) was significantly higher in the ICI group than in the chemotherapy group (p<0.001). In the ICI group, there was no significant difference in OS between patients with and without DIILD (p=0.784). A propensity score-matched analysis indicated that the first-ICI group had a significantly longer OS than the matched chemotherapy group (p<0.001).Conclusions In patients with ILD-NSCLC, ICIs were associated with significantly longer OS compared with cytotoxic chemotherapy, despite the increased risk of DIILD.