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Prospective cohort studies have provided evidence on longer-term mortality risks of fine particulate matter (PM2.5), but due to their complexity and costs, only a few have been conducted. By linking monitoring data to the U.S. Medicare system by county of residence, we developed a retrospective cohort study, the Medicare Air Pollution Cohort Study (MCAPS), comprising over 20 million enrollees in the 250 largest counties during 2000-2002. We estimated log-linear regression models having as outcome the age-specific mortality rate for each county and as the main predictor, the average level for the study period 2000. Area-level covariates were used to adjust for socio-economic status and smoking. We reported results under several degrees of adjustment for spatial confounding and with stratification into by eastern, central and western counties. We estimated that a 10 µg/m3 increase in PM25 is associated with a 7.6% increase in mortality (95% CI: 4.4 to 10.8%). We found a stronger association in the eastern counties than nationally, with no evidence of an association in western counties. When adjusted for spatial confounding, the estimated log-relative risks drop by 50%. We demonstrated the feasibility of using Medicare data to establish cohorts for follow-up for effects of air pollution. Particulate matter (PM) air pollution is a global public health problem (1). In developing countries, levels of airborne particles still reach concentrations at which serious health consequences are well-documented; in developed countries, recent epidemiologic evidence shows continued adverse effects, even though particle levels have declined in the last two decades (2-6). Increased mortality associated with higher levels of PM air pollution has been of particular concern, giving an imperative for stronger protective regulations (7). Evidence on PM and health comes from studies of acute and chronic adverse effects (6). The London Fog of 1952 provides dramatic evidence of the unacceptable short-term risk of extremely high levels of PM air pollution (8-10); multi-site time-series studies of daily mortality show that far lower levels of particles are still associated with short-term risk (5)(11-13). Cohort studies provide complementary evidence on the longer-term risks of PM air pollution, indicating the extent to which exposure reduces life expectancy. The design of these studies involves follow-up of cohorts for mortality over periods of years to decades and an assessment of mortality risk in association with estimated long-term exposure to air pollution (2-4;14-17). Because of the complexity and costs of such studies, only a small number have been conducted. The most rigorously executed, including the Harvard Six Cities Study and the American Cancer Society’s (ACS) Cancer Prevention Study II, have provided generally consistent evidence for an association of long- term exposure to particulate matter air pollution with increased all-cause and cardio-respiratory mortality (2,4,14,15). Results from these studies have been used in risk assessments conducted for setting the U.S. National Ambient Air Quality Standard (NAAQS) for PM and for estimating the global burden of disease attributable to air pollution (18,19). Additional prospective cohort studies are necessary, however, to confirm associations between long-term exposure to PM and mortality, to broaden the populations studied, and to refine estimates by regions across which particle composition varies. Toward this end, we have used data from the U.S. Medicare system, which covers nearly all persons 65 years of age and older in the United States. We linked Medicare mortality data to (particulate matter less than 2.5 µm in aerodynamic diameter) air pollution monitoring data to create a new retrospective cohort study, the Medicare Air Pollution Cohort Study (MCAPS), consisting of 20 million persons from 250 counties and representing about 50% of the US population of elderly living in urban settings. In this paper, we report on the relationship between longer-term exposure to PM2.5 and mortality risk over the period 2000 to 2002 in the MCAPS.