Background: Rs31489 in the cleft lip and palate transmembrane1-like gene (CLPTM1L) has been identifiedto be associated with lung cancer through genome-wide association studies (GWAS). However, some recentreplication studies yielded inconclusive results. Thus, we undertook this study to investigate the precise effectof rs31489 on lung cancer susceptibility. Materials and Methods: A hospital-based case-control study in 1,673Chinese subjects (611 individuals with lung cancer and 1,062 controls) and a meta-analysis among 32,199subjects (16,364 cases and 15,835 controls) were performed in this study. Results: In our case-control study,rs31489 was inversely associated with lung cancer (AC versus CC: OR=0.68, 95%CI=0.52-0.88; additive model:OR=0.68, 95%CI=0.54-0.85; dominant model: OR=0.65, 95%CI =0.51-0.84). Stratification analysis by smokingstatus showed a significant association and strong genetic effect in non-smokers but not in smokers. Our metaanalysisfurther confirmed the association, although with significant heterogeneity contributed by study designand source of controls, as shown by stratified analysis. Sensitive and cumulative analyses both indicated robuststability of our results. In addition, there was no observable publication bias in our meta-analysis. Conclusions:Overall, the findings from our replication study and meta-analysis demonstrated that CLPTM1L gene rs31489is significantly associated with lung cancer.