Rationale: In October 2014, the Food and Drug Administration approved the anti-fibrotic medications pirfenidone and nintedanib for use in patients with idiopathic pulmonary fibrosis (IPF), a progressive, highly fatal lung disease. This followed the results of two similarly-designed randomized control trials demonstrating that the medications slowed the decline in lung function over the course of the 52-week follow-up periods. There was also a trend toward improved survival with each medication, but this outcome was not statistically significant in either trial. Since their approval, there has been no real-world analysis or randomized trial comparing the effect of the anti-fibrotic medications on mortality in clinical practice.Methods: Using a large United States administrative claims database, we identified adult patients with IPF (based on ICD-9 and ICD-10 codes specific to IPF) between July 2014 and December 2017. We then split patients into two cohorts: IPF patients not receiving treatment (non-treated cohort) and patients treated with nintedanib or pirfenidone (treated cohort). One-to-one propensity score matching was used to balance patients on 23 sociodemographic and clinical variables. Cox models were used to compare outcomes between the cohorts. The primary outcome was all-cause mortality. Differences in treatment response by drug (nintedanib versus pirfenidone) were also examined.Results: A total of 1255 matched pairs were included; mean (standard deviation) follow-up was 9.9 (9.35) months. When comparing patients with IPF on treatment to those not treated, patients treated with either of the two medications had an association with a decreased risk of all-cause mortality (Hazard Ratio [HR] 0.77; 95% confidence interval [CI], 0.62 to 0.98; p value=0.03). However, this benefit was noted only through the first two years of treatment. There was no significant difference in mortality between patients on pirfenidone and those on nintedanib (HR 1.09; 95% CI, 0.75 to 1.6; p=0.65).Conclusion: Patients with IPF on treatment have a reduced risk of death compared to those not receiving treatment. However, our findings suggest that the treatment may be less effective after the initial two years of treatment. This warrants further evaluation. When comparing pirfenidone and nintedanib head-to-head, there is no difference in mortality.