It has been suggested in some studies that head injury is a risk factor for AD, and that this risk is heightened among carriers of the APOE-epsilon4 allele. We examined the effects of head injury and APOE genotype on AD risk in a large family study. A total of 2,233 probands who met criteria for probable or definite AD and their 14,668 first-degree family members (4,465 parents, 7,694 siblings, and 2,509 spouses) were ascertained at 13 centers in the United States, Canada, and Germany participating in the MIRAGE (Multi-Institutional Research in Alzheimer Genetic Epidemiology) project. Information on head injury was collected by interview of multiple informants and review of medical records. Nondemented relatives and spouses served as control subjects for this study. Odds of AD for head trauma with or without loss of consciousness were computed by comparing probands with unaffected spouses using conditional logistic regression analysis. To account for the unique biologic relationship between probands and their parents and siblings, odds of AD were computed using a generalized estimating equation (GEE) Poisson regression approach. GEE logistic regression was used to examine the joint effects of APOE genotype and head injury on the odds of AD in probands and a control group comprised of unaffected siblings and spouses. Comparison of probands with their unaffected spouses yielded odds ratios for AD of 9.9 (95% CI, 6.5 to 15.1) for head injury with loss of consciousness and 3.1 (2.3 to 4.0) for head injury without loss of consciousness. The corresponding odds derived from the comparison of probands with their parents and sibs were 4.0 (2.9 to 5.5) for head injury with loss of consciousness and 2.0 (1.5 to 2.7) for head injury without loss of consciousness. Head injury without loss of consciousness did not significantly increase the risk of AD in spouses (OR = 1.3; 95% CI, 0.4 to 4.1). The joint effects of head injury and APOE genotype were evaluated in a subsample of 942 probands and 327 controls (spouses and siblings). Head injury increased the odds of AD to a greater extent among those lacking epsilon4 (OR = 3.3) than among epsilon4 heterozygotes (OR = 1.8) or homozygotes (OR = 1.3). Head injury is a risk factor for AD. The magnitude of the risk is proportional to severity and heightened among first-degree relatives of AD patients. The influence of head injury on the risk of AD appears to be greater among persons lacking APOE-epsilon4 compared with those having one or two epsilon4 alleles, suggesting that these risk factors may have a common biologic underpinning.