Excess cholesterol is removed from the brain via hydroxylation mediated by cholesterol 24S-hydroxylase (CYP46), which is a mechanism of maintaining cholesterol homeostasis in the brain. The CYP46A1 gene has been suggested as a genetic risk factor for sporadic late-onset Alzheimer's disease (AD). In this report, we analyzed an intronic CYP46A1 single nucleotide polymorphism (SNP) in 508 sporadic AD patients and 549 controls in a Chinese Han population. Our results indicated that the distribution of CYP46A1 SNP rs754203 genotypes was significantly different in AD patients compared to controls (χ(2) = 6.59, P = 0.037). The frequency of at least one of CYP46A1 T allele (C/T or T/T) was higher in AD patients compared to controls (χ(2) = 6.58, P = 0.01). The age- and sex-adjusted odds ratio for the risk of AD in carriers of CYP46A1 T allele (C/T + T/T) was 1.69 (95 % confidence interval, 1.12-2.56). We conclude that this intronic polymorphism in CYP46A1 gene is associated with AD in a Chinese Han population, and the CYP46A1 T allele might be a risk factor for AD.