Introduction <p>Nintedanib, a tyrosine kinase inhibitor, is approved for treatment of progressive fibrosing interstitial lung disease (PF-ILD). Existing clinical safety data for nintedanib treatment of PF-ILD in Japanese patients is based on relatively few patients, therefore, further evaluation is needed. An interim report of the present surveillance has been previously published; here, we report data from the full surveillance.</p> Methods <p>Non-interventional, prospective, 2-year post-marketing surveillance evaluated the safety of nintedanib in a real-world setting in Japan, in patients with PF-ILD other than idiopathic pulmonary fibrosis or systemic sclerosis-associated ILD between October 2, 2020, and January 22, 2025. Patients newly initiated on nintedanib, 150&#xa0;mg bid or 100&#xa0;mg bid, were included. The primary outcome was the incidence of adverse drug reactions (ADRs). Other safety outcomes included the incidence of adverse events (AEs) leading to treatment discontinuation, AEs leading to death, and serious adverse events (SAEs).</p> Results <p>ADRs were reported in 246/408 (60.29%) patients; the most common were diarrhea (30.88%), nausea (8.82%), and hepatic function abnormal (8.33%). There were no noticeable differences in the incidence of ADRs between subgroups by clinical ILD diagnosis. AEs were the main reason for treatment discontinuation. AEs leading to treatment discontinuation were reported for 145 (35.54%) patients. The most common reason was diarrhea (6.86%). The adjusted annual rate of decline in forced vital capacity was − 93.2&#xa0;mL/year [SE: 65.6, 95% confidence interval − 223.1 to 36.8 (<i>n</i> = 200)].</p> Conclusions <p>The safety profile of nintedanib in clinical practice is consistent with previous reports. No new safety concerns were observed. However, the effectiveness of nintedanib in this real-world setting was not sufficient to stop disease progression, and the treatment discontinuation rate due to AEs was high.</p> Trial registration <p>NCT04559581.</p>