Abstract Background Despite the therapeutic efficacy of immune checkpoint inhibitors (ICIs) in a subset of patients, consistent and easily obtainable predictors of efficacy remain elusive. Methods This study was conducted on 644 advanced non-small cell lung cancer (NSCLC) patients treated with ICI monotherapy between April 2013 and September 2020 at the Dana-Farber Cancer Institute and Brigham and Women’s Hospital. Patient smoking history, clinicopathological characteristics, tumor mutation burden (TMB) by clinical targeted next-generation sequencing, and programmed death ligand-1 (PD-L1) tumor proportion score (TPS) by immunohistochemistry were prospectively collected. The association of smoking history with clinical outcomes of ICI monotherapy in metastatic NSCLC patients was evaluated after adjusting for other potential predictors. All statistical tests were 2-sided. Results Of 644 advanced NSCLC patients, 105 (16.3%) were never smokers, 375 (58.2%) were former smokers (median pack-years = 28), and 164 (25.4%) were current smokers (median pack-years = 40). Multivariable logistic and Cox proportional hazards regression analyses suggested that doubling of smoking pack-years is statistically significantly associated with improved clinical outcomes of patients treated with ICI monotherapy (objective response rate odds ratio = 1.21, 95% confidence interval [CI] = 1.09 to 1.36, P < .001; progression-free survival hazard ratio = 0.92, 95% CI = 0.88 to 0.95, P < .001; overall survival hazard ratio = 0.94, 95% CI = 0.90 to 0.99, P = .01). Predictive models incorporating pack-years and PD-L1 TPS yielded additional information and achieved similar model performance compared with using TMB and PD-L1 TPS. Conclusions Increased smoking exposure had a statistically significant association with improved clinical outcomes in metastatic NSCLC treated with ICI monotherapy independent of PD-L1 TPS. Pack-years may serve as a consistent and readily obtainable surrogate of ICI efficacy when TMB is not available to inform prompt clinical decisions and allow more patients to benefit from ICIs.