Objective DNA mismatch repair deficiency is not only thought to promote tumorigenesis but is also suggested to be associated with platinum-based chemotherapy treatment. In this study, we investigated the effects of two genetic polymorphisms in the hMSH2 and hMLH1 genes on the risk of epithelial ovarian cancer and the clinical outcome of patients treated with platinum-based chemotherapy. Methods A case-control study was performed in 536 epithelial ovarian cancer patients and 532 control women. Genotypes of two polymorphisms were determined by the polymerase chain reaction/ligase detection reaction method. Pearson Chi-square test was used to evaluate genotype distributions and allele frequencies in the patients and controls. Kaplan-Meier survival curves, and univariate and multivariate Cox regression models were used to analyze the effect of polymorphisms on patients' prognoses. Results The genotype and allele frequencies of the rs2303428 and rs1800734 polymorphisms were not significantly different between the case and control groups. Compared with wild homozygous genotype, the presence of variant alleles (heterozygous and variant homozygous genotypes) did not affect the risk of developing epithelial ovarian cancer. However, survival analysis showed that the rs2303428 polymorphism was related to the prognosis of epithelial ovarian cancer patients. Compared with the TT genotype, patients carrying the C allele had a shorter progression-free survival during the 3- and 5-year follow-up (HR 1.41, 95% CI 1.07 to 1.87 and HR 1.56, 95% CI 1.12 to 2.16, respectively). For the rs1800734 polymorphism, the A allele may significantly increase patients' progression-free survival compared with the GG genotype in the 5-year follow-up (HR 0.66, 95% CI 0.44 to 0.98). Conclusion Our research suggests that genetic polymorphisms in hMSH2 and hMLH1 may indicate the clinical progression of epithelial ovarian cancer patients treated with platinum-based chemotherapy.