BACKGROUNDPatients with idiopathic pulmonary fibrosis (IPF) experience debilitating symptoms. While antifibrotics may slow lung function decline, their impact on patients’ health-related quality of life (HRQoL) and disease symptoms in the real world remains unknown. RESEARCH QUESTIONWhat is the impact of pirfenidone vs no treatment on HRQoL and IPF-related symptoms of cough, dyspnea, and fatigue? STUDY DESIGN AND METHODSThis retrospective analysis included patients with IPF aged ≥ 55 years enrolled in the Pulmonary Fibrosis Foundation Patient Registry between March 2016 and December 2021. Change from baseline in patient-reported outcome measures (PROMs) including the Leicester Cough Questionnaire (LCQ), University of California, San Diego Shortness of Breath Questionnaire (UCSD SOBQ), Fatigue Severity Scale, and Short Form-6 Dimension questionnaire were assessed at Months 6, 12, and 18 in patients receiving pirfenidone vs no treatment. A marginal structure model (MSM) accounted for time-varying confounding caused by percent predicted forced vital capacity (%FVC) and percent predicted diffusing capacity of the lung for carbon monoxide. RESULTSIn the LCQ population (n = 237; pirfenidone, n = 155; no treatment, n = 82), treatment groups differed in age, insurance, and %FVC. In the unadjusted analyses, mean changes in PROMs differed numerically between treatment groups; however, based on the MSM, there were no significant differences in adjusted mean changes in PROMs. When analyzed by Gender, Age, and Physiology (GAP) score, a clinically meaningful reduction in worsening of pirfenidone vs no treatment was observed in the adjusted mean change of UCSD SOBQ at Month 12 in patients with GAP stage 2/3. INTERPRETATIONSimilar to previous findings, the difference in UCSD SOBQ scores observed in this real-world analysis suggests that patients with more advanced IPF may experience less dyspnea when receiving pirfenidone vs no treatment; further research is needed to confirm this finding.