We examined the relationships between single-nucleotide polymorphisms (SNPs) in the DNA repair gene XPD751 and the efficacy and time to disease progression (TTP) in colorectal cancer patients after platinum-based chemotherapy. Ninety-eight patients diagnosed with advanced colorectal cancer were subjected to oxaliplatin and 5-fluorouracil combination therapy. DNA was extracted from venous blood before chemotherapy. Polymerase chain reaction-restriction fragment length polymorphism analysis was used to detect XPD751 SNPs. The relationship between genotypes and prognosis was compared. The frequencies of the XPD751 Lys/Lys, Lys/Gln, and Gln/Gln genotypes were 76 (77.55%), 17 (17.35%), and 5 (5.10%), respectively. The efficiency of XPD751 Lys/Lys, Lys/Gln and Gln/Gln genotypes were 50.00, 29.41, and 20%, respectively. The efficiency rate between XPD751 Lys/Lys and Lys/Gln showed a significant difference (c² = 4.04, P < 0.05). After adjusting for gender, age, and metastasis location, chemotherapy failure in patients carrying XPD751 Lys/Gln was 3.404-fold higher than in patients carrying the Lys/Lys genotype. Median TTP was 304 days (10.1 months) and median TTP in patients with XPD751 Lys/Lys and ≥1 Gln genotype was 340 and 87 days. After comparing TTP in patients carrying Lys/Lys and patients carrying ≥1 Gln, the difference was significant. SNPs in the DNA repair gene XPD751 may be associated with oxaliplatin and 5-fluorouracil chemotherapy sensitivity in colorectal cancer patients. These polymorphisms may be associated with TTP in patients with advanced colorectal cancer after first-line chemotherapy of oxaliplatin. XPD751 SNPs may be predictive factors of prognosis in colorectal cancer patients receiving oxaliplatin and 5-fluorouracil chemotherapy.