Background <p>Studies suggest that the complement pathway may play a role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). We evaluated associations between complement pathway gene expression and clinical outcomes in patients with IPF.</p> Methods <p>RNA was extracted from blood samples collected at enrollment into the IPF-PRO Registry. Patients were divided into discovery (<i>n</i> = 261) and validation (<i>n</i> = 609) cohorts. Patients were followed prospectively while receiving usual care. Using Cox proportional hazards models, we evaluated associations between expression of 45 complement pathway genes and three clinical outcomes. Analyses were unadjusted and adjusted for clinical variables at enrollment.</p> Results <p>Eight complement pathway genes (CR1, CD59, C2, C1QTNF6, ITGB3, C1QBP, CD55, CR2) were associated with ≥ 1 outcome in the discovery cohort and evaluated in the validation cohort. In the discovery cohort, in unadjusted analyses, higher expression of the membrane-bound complement regulators CR1, CD55, and CD59 was associated with increased risk (hazard ratios [HRs]: 1.75 [95% CI 1.27, 2.41], 1.40 [1.06, 1.85] and 1.62 [1.17, 2.23], respectively), and higher expression of complement pathway component C2 with a decreased risk (HR 0.75 [0.61, 0.91]), of disease progression (absolute decline in forced vital capacity % predicted ≥ 10%, death, or lung transplant). Associations of CR1, CD55 and C2 with disease progression persisted in the validation cohort in adjusted analyses. In the discovery cohort, in unadjusted analyses, higher expression of CR1 and CD55 was associated with increased risk (HRs 2.66 [1.68, 4.23] and 1.90 [1.24, 2.93], respectively), and higher expression of C2 with a decreased risk (HR 0.61 [0.46, 0.80]), of respiratory death; associations with CR1, CD55, and C2 persisted in the validation cohort in adjusted analyses. In the validation cohort, increased expression of C2 was associated with reduced risk of respiratory hospitalization in adjusted analyses (HR 0.65 [0.50, 0.83]). Principal component analysis identified a composite score including complement components and regulators that was associated with increased risk of disease progression and respiratory death in both cohorts.</p> Conclusions <p>Higher expression of complement regulators and lower expression of complement components, individually and in combination, may be biomarkers of progression of IPF.</p> Trial registration <p>ClinicalTrials.gov (NCT01915511). Registered 5 August 2013, <a href="https://clinicaltrials.gov/ct2/show/NCT01915511">https://clinicaltrials.gov/ct2/show/NCT01915511</a>.</p>