BACKGROUND: Whether mutations in the hemochromatosis (HFE) gene increase cardiovascular disease risk is still undetermined. The main reason is the low frequency of the mutations, in particular of the compound C282Y/H63D genotype. We combined the data of 11 observational studies for an individual patient data meta-analysis. METHODS AND RESULTS: Individual patient data were obtained from published as well as unpublished studies that had information available on the C282Y mutation as well as the H63D mutation in relation to coronary heart disease risk. Individual records were provided on each of the 53 880 participants in 11 studies. In total, 10 541 patients with coronary events were documented, of whom 5724 had an acute myocardial infarction. The crude and adjusted association between HFE genotypes and coronary events was examined by logistic regression analysis. We explored potential effect modification of the association between traditional cardiovascular risk factors and coronary events by HFE genotypes. After full adjustment, the odds ratio for coronary heart disease was 1.12 (95% CI, 0.92 to 1.37) for subjects with the compound heterozygous (C282Y/H63D) genotype relative to those with the wild-type/wild-type genotype. The odds ratios for C282Y/C282Y, C282Y/wild-type, H63D/H63D, and H63D/wild-type were 0.78 (95% CI, 0.49 to 1.26), 0.98 (95% CI, 0.90 to 1.07), 1.16 (95% CI, 0.97 to 1.38), and 1.07 (95% CI, 1.00 to 1.14), respectively. There was no evidence for effect modification. CONCLUSIONS: The results of this large individual patient data meta-analysis do not support the view that HFE gene mutations are associated with an increased risk of coronary heart disease or acute myocardial infarction.