Whether the variations in the hemochromatosis (HFE) gene increase Alzheimer's disease (AD) risk is still undetermined. We performed a meta-analysis in order to systematically summarize the possible association. Studies were identified by searching PUBMED, Web of Science and EMBASE databases complemented with screening the references of the retrieved studies. The association was measured using random-effect or fixed-effect odds ratio (OR) combined with 95% confidence intervals (CIs) according to the studies' heterogeneity. For C282Y polymorphism, we did not find any association using data from 22 studies including 4,365 cases and 8,652 controls. For H63D polymorphism, on the basis of 2,795 cases and 7,424 controls from 17 studies, we observed a significant association (allele contrast: OR = 0.902, 95% CI = 0.819-0.994, P = 0.037; minor-allele-dominant model: OR = 0.887, 95% CI = 0.790-0.996, P = 0.043). No publication bias was detected in this meta-analysis. The synthesis of available evidence supports mutant of HFE H63D polymorphism plays a protective role for AD risk.