It is well known that oxidative stress plays an important role in atherosclerosis and age-related diseases. The antioxidant properties of the Human Paraoxonase gene family (PON1, 2, 3) have been widely investigated, as well as a possible role of the such gene family in cardiovascular disease. In this study, we investigated the relationship between the C311S PON2 polymorphism and the prognosis of acute myocardial infarction (AMI). We analyzed the PON2 C311S polymorphism in 442 elderly patients who had experienced an AMI. PON2 C311S genotypes were identified by PCR based analysis and analyzed as C- (SS genotype) or C+ (CS+CC) carriers. After 1 year of follow-up, the cardiovascular mortality rate in a sub-group of 295 AMI patients was calculated. We found that AMI patients carrying CS+CC genotypes (C+ carriers) had a history of type 2 diabetes mellitus, low levels of HDL-cholesterol and higher levels of TroponinT (TnT). Furthermore, we found that C+ carrier patients with low levels of HDL-cholesterol had an increased risk for mortality after 1 year of follow-up (Log Rank=11.45, p=0.001). Our study suggests a possible role for PON2 C311S polymorphism in the pathogenesis of cardiac ischemic damage. Patients with at least one C allele (C+ carriers) represent a category of subjects at a higher risk for the development of AMI with a worse prognosis. Our findings suggest the need for a more careful clinical monitoring in older persons with such characteristics.