Background: The mRNA levels of C2CD4A and C2CD4B were dysregulation in lung cancer (LC). We aim to evaluate the role of C2CD4A/B variants in LC susceptibility. Methods: 710 cases with LC and 710 healthy controls were enrolled in the study. The genotyping of twelve SNPs in C2CD4A/B were carried out by Agena MassARRAY system. Odds ratios (ORs) and 95% confidence intervals (CIs) for multiple inheritance models were calculated by logistic regression analysis to assess the relationship between selected variants and the predisposition of LC. Results: Rs8037894 (OR = 0.81, p = 0.005), rs7172432 (OR = 0.83, p = 0.013), rs11856307 (OR = 0.86, p = 0.043), and rs1436953 (OR = 0.79, p = 0.002) were related to with the reduced risk of LC. Stratified analysis showed that this association was especially remarkable in the subgroup at aged > 60 years, males, subjects with BMI >24 kg/m2, smokers and non-drinkers. We also found that C2CD4A/B variants were associated with lymph nodes metastasis and pathological type (adenocarcinoma and small cell carcinoma). Conclusions: Our results firstly displayed that C2CD4A/B polymorphisms served as protective factors for LC predisposition in a Chinese Han population. These findings could provide new biological insight into the understanding of C2CD4A/B genes on LC pathogenesis.