Purpose Sirolimus has purported advantages in lung transplant maintenance therapy, such as anti-fibrotic, anti-proliferative, and anti-aging effects, which may help improve survival. Methods Among U.S. lung transplant recipients from 2003-2016 in the United Network for Organ Sharing (UNOS) dataset, we compared sirolimus [SIR] (n=219) to mycophenolate mofetil [MMF] (n=5482), within a tacrolimus-based regimen. The SIR group consisted of patients on SIR within 1 year post-transplant, since prophylactic SIR initiation is usually delayed by up to 1 year to avoid the risk of bronchial anastomotic dehiscence and other complications. Due to the delayed initiation of SIR, this study was restricted to patients alive at 1 year in both groups, to prevent immortal time bias. All patients in both groups were free of bronchiolitis obliterans syndrome and malignancy at 1 year, to exclude these common rescue uses of SIR. We also assessed survival for SIR and MMF after subdividing by whether or not patients received induction therapy (with basiliximab, daclizumab, antithymocyte globulin, or alemtuzumab). Survival comparisons were based on Kaplan-Meier estimates and Cox multivariable regression utilizing multiple imputation to handle missing data. Results SIR had better survival than MMF: median (MS) 8.9 vs 7.1 yr.; adjusted Hazard Ratio (HR)=0.71, p=0.003. When subdividing by whether patients received induction, SIR with no induction had the best survival (MS=10.7 yr.; HR=0.48, p=0.002), followed by SIR with induction (MS=7.9 yr.; HR=0.90, p=0.45), MMF with induction (MS=7.4 yr.; reference group), and MMF with no induction (MS=6.8 yr.; HR=1.15, p=0.01). Conclusion Sirolimus, initiated within 1 year after lung transplantation in a tacrolimus-based regimen, may improve survival compared to MMF. National data representing the U.S. lung transplant population suggest that sirolimus + tacrolimus maintenance with no induction therapy is associated with a median survival of approximately 10 years.