Introduction/Objectives <p>Treatment discontinuation of nintedanib is an important clinical issue in patients with connective tissue disease–associated interstitial lung disease (CTD-ILD). This study aimed to evaluate real-world retention of nintedanib across CTD subtypes and to explore factors associated with treatment discontinuation.</p> Methods <p>We conducted a single-center retrospective study of consecutive patients with CTD-ILD who initiated nintedanib between June 2019 and December 2024. Clinical data, including baseline characteristics, concomitant therapies, and treatment outcomes, were collected. The primary outcome was the 48-week retention rate. Kaplan–Meier analysis and Cox proportional hazards models were used to evaluate factors associated with treatment discontinuation.</p> Results <p>A total of 92 patients were included (rheumatoid arthritis [RA], <i>n</i> = 25; idiopathic inflammatory myopathy [IIM], <i>n</i> = 25; systemic sclerosis [SSc], <i>n</i> = 21; microscopic polyangiitis [MPA], <i>n</i> = 10; Sjögren disease [SjD], <i>n</i> = 9). The 48-week retention rate was 82.6%, with a median treatment duration of 978&#xa0;days (IQR, 586–1356). Retention was lowest in RA, with higher rates observed in other CTD subtypes. Stratified analyses showed that this difference was evident in patients aged &lt; 65&#xa0;years (<i>p</i> = 0.001) and those receiving an initial dose of 300&#xa0;mg/day (<i>p</i> = 0.003), but not in older patients or those receiving &lt; 300&#xa0;mg/day. In univariable analysis, RA (HR 3.10, <i>p</i> = 0.024) and an initial dose of 300&#xa0;mg/day (HR 2.67, <i>p</i> = 0.050) were associated with discontinuation. However, RA was not independently associated with discontinuation after adjustment for age and initial dose in the exploratory multivariable analysis.</p> Conclusions <p>Nintedanib showed favorable retention in CTD-ILD. Although retention appeared lower in RA, this difference may be influenced by patient characteristics such as age and initial dosing. Individualized dose selection and appropriate management of adverse events may improve treatment persistence.</p> <p><Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec colname="c1" colnum="1" /> <colspec colname="c2" colnum="2" /> <tbody> <row> <entry align="left" nameend="c2" namest="c1"> <p>Key Points</p> <p>• Nintedanib showed favorable 48-week retention in patients with CTD-ILD in a real-world setting.</p> <p>• Lower retention observed in RA was influenced by age and initial dosing, rather than disease subtype alone.</p> </entry> </row> </tbody> </tgroup> </Table></p>