PURPOSE: Excessive activation of the complement system has been associated with fibrosis and other adverse outcomes in multiple organ systems. We hypothesized that lung transplant (LTx) recipients with a genetic predisposition to complement activation would be at increased risk for chronic lung allograft dysfunction (CLAD). METHODS: We conducted a retrospective study of adult primary LTx recipients from 2008-2015 at Barnes-Jewish Hospital. Genotyping was done using the Taqman assay on salivary DNA for rs2230199, a known functional polymorphism (C3R102G, minor allele frequency (C)=15%), which is associated with more efficient complement activation on hemolysis assays. Our primary outcome was CLAD-free survival. Analysis included Kaplan-Meier curves with Chi-Square testing, and a multivariable Cox regression model for CLAD-free survival. External validation was conducted in LTx recipients at the University of California, San Francisco. RESULTS: 176 patients were included. 111 (63%) had wild-type C3 (G/G), whereas 64 (36%) had the C3R102G polymorphism (57 - C/G, 7 - C/C). C3R102G was associated with increased risk for CLAD (HR 2.71, 95% CI 1.27 - 5.79, p= 0.01). There was no increased risk for primary graft dysfunction or acute cellular rejection. In a multivariable Cox-proportional hazards model including age, sex, race, LTx type, and pre-LTx diagnosis, C3R102G was associated with increased risk of the composite outcome (CLAD or death, Figure). In the validation cohort, C3R102G remained a significant risk factor for this composite outcome on multivariable analysis (n=322, aHR 1.5, 95% CI 1.03 - 2.2, p=0.03). In a subgroup analysis in both cohorts, C3R102G remained a significant risk factor for CLAD or death when accounting for age, lung allocation score, post-LTx Gram-negative infection and donor-specific antibodies. CONCLUSION: In two independent cohorts, recipient C3R102G risk alleles are associated with worse CLAD-free survival. These findings support a mechanistic link between complement activation and CLAD.