OBJECTIVES: Idiopathic Pulmonary Fibrosis (IPF) is a rare, progressive disease of unknown aetiology with a dismal median survival of 3 years. To date, two antifibrotic agents are commercialised in Spain to treat IPF: nintedanib and pirfenidone. The aim of this study is to compare their relative cost-effectiveness from the Spanish setting. METHODS: A previously developed Markov model simulating a hypothetical cohort of patients with IPF followed up for their lifetime was adapted to the Spanish National Health System perspective. Relative effectiveness was calculated from a network meta-analysis using data from each pivotal trial. Mortality, loss of lung function and acute exacerbations were included to measure efficacy outcomes while toxicity (serious adverse events) and tolerability (overall discontinuation) were included to measure safety. The baseline risk of each event was estimated using data from the control arm of nintedanib clinical trials (TOMORROW, INPULSIS-1, INPULSIS-2). An annual discount rate of 3% was set for both costs and health benefits. Sensitivity analyses (deterministic and probabilistic) tested the impact of alternate efficacy and safety outcomes, costs, time horizons and utility values, as well as differential rates of discontinuation. The cost inputs came from Spanish sources, reported in 2016 euros. RESULTS:  Nintedanib yielded higher quality-adjusted life years (QALY) than pirfenidone (3.66 QALY vs. 3.62 QALY, respectively) and was associated with lower total costs (€6,854 less) mainly due to fewer acute exacerbations. Consequently, nintedanib dominated pirfenidone due to better effectiveness and lower costs. One-way deterministic and probability sensitivity analyses showed that the model was robust to most variations. If pirfenidone price was 25% lower, nintedanib would still dominate pirfenidone. CONCLUSIONS:  In the Spanish setting, nintedanib was found to be economically dominant (less costly and more effective) over pirfenidone, mainly due to fewer acute exacerbations.