The cyclooxygenase-2 enzyme (COX-2) is of particular importance in the inflammatory response and recent findings have demonstrated a considerable role in Alzheimer's disease (AD) pathogenesis. In order to assess the possible putative role of a COX-2 polymorphism (765G/C) in AD, we examined its distribution in 161 community-based controls and 168 AD clinic-based cases previously recruited from memory disorder clinics in Tampa and Miami, Florida. There were no significant differences between the two groups in age/age of onset or gender. A significant difference was observed in the distribution of the COX-2 -765 alleles between AD cases and controls (chi(2) = 6.565, p = .010; OR = .596; CI = [.401-.888], p = .011), with the frequency of the C allele being higher in controls. In addition, a significant difference was observed for this polymorphism by genotype (chi(2) = 6.561, p = .038) and by presence or absence of C+ genotypes (chi(2) = 6.207, p = .013; OR = .464, CI = [.351-.885], p = .013). In this sample, the C allele of COX-2 -765 promoter polymorphism is associated with decreased risk of Alzheimer's disease, a finding which further supports the involvement of COX-2 in AD etiology.