Background: XPC, XPF, TP53 and GSTP1 genes act on repair and detoxification of ultraviolet (UV) radiation-induced DNA damage, which are related to cutaneous melanoma (CM) development and progression. The DNA repair ability is variable in humans, since the genes enrolled in the process are polymorphic. This study aimed to evaluate whether XPC c.2815A > C, XPF c.2505T > C, TP53 c.215G > C and GSTP1 c.313A > G polymorphisms are associated with survival of CM patients. Methods: We analyzed 237 CM patients diagnosed from 2000 to 2014 at the University of Campinas. Genomic DNA of patients was analyzed by polymerase chain reaction and restriction fragment length polymorphism assays, for discrimination of pertinent genotypes. Relapse-free survival (RFS) and overall survival (OS) times were calculated using Kaplan-Meier estimate probabilities and differences between survival curves were analyzed by the log-rank test. The prognostic impact of genotypes was examined using univariate and multivariate Cox regression analyses. Results: The median follow-up time of all patients enrolled in this study was 52 months (range: 0.9-175.1 months). At 60 months of follow-up, patients with XPC CC genotype presented shorter RFS (59.6% vs. 74.0%, P= 0.03), and patients with XPF CC genotype presented a tendency for short RFS (48.0% vs. 73.5%, P= 0.06) and a shorter OS (71.8% vs. 85.6%, P< 0.001) than those with other genotypes (Kaplan-Meier estimates). Patients with XPC CC genotype (HR: 1.85, P = 0.03) and XPF CC genotype (HR: 3.59, P= 0.01) had more chance to recurrence than those with other genotypes in univariate and multivariate Cox regression analyses, respectively. Patients with XPF CC (HR: 3.52, P= 0.001) and XPF TC+CC (HR: 9.40, P= 0.02) genotypes were associated with greater risk of progressing to death than other genotypes in univariate and multivariate Cox regression analyses, respectively. Conclusions: The data suggest, for the first time, that inherited abnormality in DNA repair pathway related to XPC and XPF polymorphisms influence prognosis of CM patients. These findings, once validated in additional studies, will contribute to individualize high-risk patients, who deserve to receive a closer follow-up and/or adjuvant therapy.