Chemotherapy based on platinum compounds is the standard treatment for NSCLC patients with EGFR wild type, and is also used as second line in mutated EGFR patients. Nevertheless, this therapy presents poor clinical outcomes. ERCC1, ERCC2, XRCC1, MDM2, MTHFR, MTR, and SLC19A1 gene polymorphisms may contribute to individual variation in response and survival to platinum-based chemotherapy. The aim of this study was to investigate the influence of these polymorphisms on response and survival of NSCLC patients treated with platinum-based chemotherapy. A retrospective-prospective cohorts study was conducted, including 141 NSCLC patients. Polymorphisms were analyzed by PCR real-time with Taqman® probes. Patients with ERCC1 rs3212986-GG (p = 0.0268; OR = 2.50; CI95% = 1.12-5.69) and XRCC1 rs25487-GG (p = 0.0161; OR = 2.99; CI95% = 1.26-7.62) genotype showed significantly better ORR. Cox survival analysis revealed that patients carrying the MDM2 rs1690924-GG genotype (p = 0.0345; HR = 1.99; CI95% = 1.05-3.80) presented higher risk of death. Furthermore, carriers of MTR rs1805087-A alleles (p = 0.0060; HR = 8.91; CI95% = 1.87-42.42) and SLC19A1 rs1051266-AA genotype (p = 0.0130; HR = 1.74; CI95% = 1.12-2.68) showed greater risk of progression. No influence of ERCC1 rs11615, ERCC2 rs13181, ERCC2 rs1799793, XRCC1 rs1799782, MDM2 rs1470383, MTHFR rs1801131, and MTHFR rs1801133 on platinum-based chemotherapy clinical outcomes was found. In conclusion, our results suggest that ERCC1 rs3212986, XRCC1 rs25487, MDM2 rs1690924, MTR rs1805087, and SLC19A1 rs1051266 gene polymorphisms may significantly act as predictive factors in NSCLC patients treated with platinum-based chemotherapy.