Background. Elevated systemic levels of myeloperoxidase (MPO) have been associated with unfavourable clinical outcomes. In the present study, we evaluate the impact of MPO, a pro-oxidant enzyme that catalyzes the initiation of lipid peroxidation and affects nitric oxide levels, on the risk of all-cause mortality in a large population of frail octogenarians and nonagenarians living in community. Methods We analyzed data from the Aging and Longevity Study in the Sirente Geographic Area (ilSIRENTE Study), a prospective cohort study that collected data on all individuals aged 80 years and older living in a mountain community (n = 363). The main outcome measure was the risk of death after 4 years of follow-up. Participants were divided into three groups based on MPO tertiles: lower tertile ≤ 61.5 μg/L (n = 120), intermediate tertile 61.6-140.6 μg/L (n = 120), and higher tertile ≥140.7 μg/L (n = 123). Results A total of 150 deaths occurred during 4-years follow-up. The mean MPO level was 170.8 ± 177.5 μg/L among those who died compared with 135.4 ± 142.4 μg/L among survivors (p =. 03). Individuals in the highest MPO tertile had higher risk of mortality (40% [60/123]) compared with those in the lower tertile (26% [39/120]). After adjusting for potential confounders, compared with participants in the lower tertile, those in the higher tertile had a hazard ratio for mortality of 1.97 (95% confidence interval: 1.02-3.80). Conclusion Our Results obtained from a representative sample of very old and frail elderly individuals expand the knowledge that low levels of MPO are associated with better survival. © The Author 2009. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved.