Genetic variations in the XPD gene may increase cancer susceptibility by affecting the capacity for DNA repair. Several studies have investigated this possibility; however, the conclusions remain controversial. Therefore, we did a systematic review and executed a meta-analysis to explore the association. From 56 studies, a total of 61 comparisons included 25,932 cases and 27,733 controls concerning the Lys 751Gln polymorphism; 35 comparisons included 16,781 cases and 18,879 controls in the case of Asp 312 Asn were reviewed. In this analysis, small associations of the XPD Lys 751 Gln polymorphism with cancer risk for esophageal cancer [for Lys/Gln versus Lys/Lys: odds ratio (OR), 1.34; 95% confidence interval (95% CI), 1.10-1.64; for Gln/Gln versus Lys/Lys: OR, 1.61; 95% CI, 1.16-2.25] and acute lymphoblastic leukemia (for Gln/Gln versus Lys/Lys: OR, 1.83; 95% CI, 1.21-2.75) are revealed. Overall, individuals with the Gln/Gln genotype have a small cancer risk compared with Lys/Lys genotype for the reviewed cancer in total (OR, 1.10; 95% CI, 1.03-1.16). Subtle but significant cancer risk was observed for the XPD Asp 312 Asn polymorphism in bladder cancer (for Asp/Asn versus Asp/Asp: OR, 1.24; 95% CI, 1.06-1.46). No significant associations were found for other cancers separately and all the reviewed cancer in total assessed for the Asp 312 Asn polymorphism. Our study suggests that XPD is a candidate gene for cancer susceptibility regardless of environmental factors.