DNA damage repair is frequently dysregulated in advanced prostate cancer and has been linked to cancer susceptibility and survival outcomes. The aim of this study is to assess the influence of genetic variants in DNA damage repair pathways on the prognosis of prostate cancer. Specifically, 167 single nucleotide polymorphisms (SNPs) in 18 DNA damage repair pathway genes were assessed for association with cancer-specific survival (CSS), overall survival (OS), and progression-free survival (PFS) in a cohort of 630 patients with advanced prostate cancer receiving androgen deprivation therapy. Univariate analysis identified four SNPs associated with CSS, four with OS, and two with PFS. However, only MSH2 rs1400633 C > G showed a significant association upon multivariate analysis and multiple testing adjustments (hazard ratio = 0.75, 95% confidence interval = 0.63–0.90, p = 0.002). Furthermore, rs1400633 risk allele C increased MSH2 expression in the prostate and other tissues, which correlated with more aggressive prostate cancer characteristics. A meta-analysis of 31 gene expression datasets revealed significantly higher MSH2 expression in prostate cancer than in normal tissues (p < 0.001), and this high expression was associated with a poor prognosis of prostate cancer (p = 0.002). In summary, we identified MSH2 rs1400633 as an independent prognostic biomarker for prostate cancer survival, and the association of MSH2 with cancer progression lends relevance to our findings.