We aimed to assess the role of polymorphisms of the XRCC1 Arg194Trp, XRCC1 Arg399Gln, ERCC5 His1104Asp, and ERCC5 His46His genes on clinical outcomes of advanced non-small cell lung cancer (NSCLC) patients receiving platinum-based chemotherapy regimens. A total of 378 NSCLC patients were asked to participate within 1 month after diagnosis between January 2005 and January 2006, and they were followed up until November 2011. Genomic DNA of the four genes was extracted using the Qiagen Blood Kit. Results showed that individuals with XRCC1 399A/A and ERCC5 46T/T genotypes were more likely to show positive responses to chemotherapy, with odds ratio (OR) = 2.27 and 95% confidence interval (CI) = 1.64-6.97, and OR = 1.90, CI = 1.10-3.28, respectively. The XRCC1 399A/A genotype was significantly associated with longer progression-free survival (PFS) and overall survival (OS) rates, and the hazard ratios (HRs) (95%CI) were 0.48 (0.25-0.88) and 0.51 (0.26-0.98), respectively. Similarly, NSCLC patients carrying the ERCC5 46T/T genotype were more likely to show increased PFS and OS, with HRs (95%CI) of 0.47 (0.22-0.82) and 0.52 (0.31-0.96), respectively. In conclusion, our study indicated that XRCC1 Arg399Gln and ERCC5 His46His might significantly influence the response to chemotherapy, and the two genetic polymorphisms are suggested to be routinely detected to determine NSCLC patients that are more likely to benefit from chemotherapy.