Lung cancer is the greatest contributor to tumor-derived death. Traditionally, platinum-based chemotherapies are the primary treatment for most patients. However, intrinsic drug resistance and side effects limit the efficacy of platinum-based chemotherapies. Previous studies demonstrated that Pol ζ can modulate cellular sensitivity to chemotherapy. The primary aim of this study was to investigate the potential role of the polymorphism of Pol ζ in platinum-based chemotherapy tolerance and side effects. A total of 663 patients who were newly histologically diagnosed with advanced NSCLC were enrolled. Their treatment response was classified into four categories: complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). The gastrointestinal and hematological toxicity incidence was assessed twice a week during the entire first line of treatment. Thirteen SNPs of REV3 and REV7 were genotyped. The associations between SNPs and the treatment response or toxicity were analyzed with a logistic regression model. We discovered that five SNPs were correlated with the treatment response. Specifically, rs240969 was significantly associated with the treatment response, after a Bonferroni correction, in smokers and a combined cohort (P=0.048 and P=0.0082, respectively) as well as with rs3218573 in smokers (P=0.036). In addition, we discovered that the incidence of grade 3 or 4 gastrointestinal toxicity was significantly higher in patients carrying a G/G genotype of rs240966 or an A allele of rs456865. We also identified that five SNPs, namely rs240966, rs4945880, rs465646, rs2233025 and rs2336030, that were correlated with an increased risk of grade 3 or grade 4 hematologic toxicity. The REV3 and REV7 polymorphisms are in a catalytic subunit and an accessory subunit of Pol ζ, respectively, and participate in platinum-chemotherapy tolerance and side effects. Key words: REV3, REV7, Pol ζ, platinum-based chemotherapies, translesion synthesis, toxicityLung cancer is the highest contributor to cancer-related deaths, and non-small cell lung cancer (NSCLC) accounts for nearly 80% of all lung cancer deaths [1]. The incidence rate of lung cancer is rapidly rising due to tobacco use, air pollution, and other cancer-causing factors [2]. Although targeted therapy is very efficient and tremendously improves the progress-free survival (PFS) and overall survival (OS) of lung cancer patients [3][4][5], however,over 70% of patients lack the positive biomarkers that are considered necessary for platinum-based chemotherapies as the traditional front-line treatment [6,7]. The efficacy of platinum-based chemotherapies is severely limited by intrinsic drug resistance. In addition, while platinum can kill uncontrollably dividing tumor cells by coupling to DNA and terminating the replication of DNA, normal cells will also be inevitably damaged [8].Previous studies have shown that DNA repair systems play an essential role in platinum-based chemotherapy tolerance [8][9][10][11]. DNA inter-or intra-crosslinking cause...