Lung cancer is the leading cause of tumor-derived death. Although target therapy is proven very efficient, traditionally platinum-based chemotherapies are still primary treatment for most patients. Platinum can suppress the tumor growth and impair normal cells together. The primary aim of the present study was to study the potential role of translesion synthesis (TLS) that might play in platinum-chemotherapy tolerance and side-effect. In present study, a total of 663 patients who were newly histologically diagnosed with advanced NSCLC (aNSCLC) were enrolled. Treatment response was classified into four categories: complete response, partial response, stable disease, and progressive disease. Incidence of gastrointestinal and hematological toxicities was assessed twice a week during the whole first-line treatment. Eleven SNPs of POLK were genotyped. The associations between SNPs and treatment response or toxicity were analyzed with logistic regression model. Cox regression was used for survival analysis between SNPs and progression-free survival or overall survival. We identified that rs3213801 and rs5744533 showed complete linkage in the present study, and they were significantly associated with treatment response (adjusted P = 0.044), together with rs5744655 (adjusted P = 0.039). rs1018119 was correlated with gastrointestinal toxicity in smokers specially (adjusted P = 0.041). Besides, rs3756558 was associated with hematological toxicity and overall toxicity in smokers and combined cohort with additive model. We also identified the significant association between two SNPs, rs10077427 and rs5744545, and PFS. The polymorphism of POLK, an important gene in TLS, participates in platinum-chemotherapy tolerance and side-effect.