Xeroderma pigmentosum group D (XPD) participates in DNA unwinding during nucleotide excision repair, which may alter the efficacy of platinum-based chemotherapy. We analyzed the influence of codon 751 Lys-->Gln polymorphism of XPD on its protein expression levels, clinico-pathological features, and outcome of 188 Chinese patients with metastatic colorectal carcinoma (CRC) that had been treated with first-line Oxaliplatin + Leucovorin + 5-Fluorouracil (FOLFOX-4) chemotherapy. The results showed that in comparison with Caucasian populations, a remarkably lower prevalence of Lys/Gln genotype was noted (16%, n = 30). No between-group difference in XPD protein expression of patients with or without this polymorphism was noted (56.5%vs 59.7%; P = 0.783). Patients with Gln751 allele have a significantly lower response to FOLFOX-4 treatment (36.7%vs 58.2%, P = 0.03), and shorter progression-free (7 vs 11 months; P < 0.01) and overall (14 vs 22 months; P < 0.01) survivals. The incidence of grade 3/4 oxaliplatin-neuropathies was very similar in both groups (13.3%vs 16.5%; P = 0.67). By adjusted analysis, this polymorphism was further identified as an independent prognostic factor (P = 0.03). These data suggest that Asian populations have a significantly lower prevalence of codon 751 Lys/Gln polymorphism in XPD, which could be a key determinant for good response to oxaliplatin-based treatment and favorable outcomes.