Background: Although associations between particulate matter <2.5 microns (PM2.5) and cardiovascular disease (CVD) and mortality are well-established, less is known regarding the joint impact of PM2.5 and neighborhood socioeconomic status (nSES). Our objective was to investigate this interaction in a nationwide cohort of U.S. women. Methods: We used time-varying Cox proportional hazards models, conditioned on age and calendar time, to assess main and interaction effects of PM2.5 and nSES on risk of CVD (stroke, myocardial infarction) and mortality among 100,257 women in the Nurses’ Health Study between 1986 and 2008. Incident CVD (n=6,445) and mortality (n=10,186) cases were ascertained from medical or death record reviews. We created Census tract-level nSES scores by summing z-scores (where increasing scores were associated with affluence) of selected nSES metrics (e.g., race, education, income, home value, nativity, unemployment), and calculated time-varying 24-month average PM2.5 exposure using residential address history. Models were adjusted for time-varying demographic, lifestyle (e.g., diet, physical activity, smoking), and individual-level SES factors. Results: In multivariable adjusted models, increases in nSES (Hazard Ratio [HR]CVD: 0.98, 95% Confidence Interval [CI]: 0.97, 0.99; HRmortality: 0.99, 95% CI: 0.99, 1.00, per 1 unit increase) and PM2.5 (HRCVD: 1.03, 95% CI: 0.95, 1.12; HRmortality: 1.04, 95% CI: 0.97, 1.11, per 10 µg/m3 increase) were associated with incident CVD and mortality rates, although the associations with PM2.5 did not reach statistical significance. The interaction between PM2.5 and nSES was statistically significant for CVD risk (p<0.001) and mortality (p<0.013); associations with mortality were strongest among the least affluent neighborhoods, while associations with CVD were weakest in areas of least and greatest affluence. Conclusions: Our results suggest that PM2.5 and nSES exposures are associated with small changes in rates of mortality and CVD incidence. These exposures interact in a complex fashion, even within a relatively demographically homogeneous cohort of women.