Several studies have shown that a common insertion (I)/deletion (D) polymorphism of angiotensin-converting enzyme (ACE) gene may confer an increased risk of late-onset Alzheimer disease (LOAD). However, the result has not been replicated by all studies. In order to clarify the role of the polymorphism for the occurrence of LOAD in Chinese and the possibility of a synergistic effect with the apolipoprotein E allele 4 on the risk of Alzheimer disease, we examined the ACE and APOE genotypes in a Chinese sample consisting of 104 sporadic LOAD patients and 128 healthy controls. An obvious difference of allelic and genotypic distributions of ACE I/D polymorphism between cases and controls was observed (chi2 = 6.61, df = 2, p = 0.037 by genotype; chi2 = 4.67, df = 1, p = 0.031 by allele). And ACE I allele carriers showed an increased risk for LOAD developing (chi2 = 6.59, df = 1, p =0.01, OR = 2.91, 95% CI 1.25-6.77). After stratifying by APOE epsilon 4 status, the increased LOAD risks associated with I allele carriers only in the APOE epsilon 4 noncarriers was seen (chi2 = 4.12, df = 1, p = 0.042). Logistic regression analysis of total subjects demonstrated a more than sevenfold increase in the risk of developing LOAD in subjects carrying both the ACE I allele and the APOE epsilon 4 (OR = 7.39, 95% CI 2.50-21.89, p < 0.001). Our data revealed that ACE I/D polymorphism is considered to be an additional risk factor, which has strong synergistic interaction with APOE epsilon 4 on the risk of LOAD.