Genetic variants in the paraoxonase (PON) gene cluster, particularly a single C/T promoter polymorphism (rs 705381) in the PON-1 gene, have recently been associated with Alzheimer's disease (AD). The T allele, in particular, presents an increased risk for the development of AD. Here, we investigate the potential role of this polymorphism in an Italian case-control population consisting of 306 sporadic AD patients and 275 controls, and also evaluate a possible interaction with the ApoE genotype. No association between the PON-1 polymorphism and AD was observed. The T allele frequency was slightly over-represented in AD patients compared to the controls, but this was far from being statistically significant. Our sample was evaluated to have 97.3% power to detect an OR of 2.0 (64.3% power with OR=1.5) at an alpha level of 0.05. No evidence of an interaction between the T risk-allele and the ApoE epsilon4 allele status and no effect of the PON-1 polymorphism on age at onset was detected. Our results do not support other studies indicating that the PON-1 promoter polymorphism plays a major role in AD, suggesting that other large studies are necessary to further elucidate the effect of PON on the development of the disease in the general population.