Background: Evidence indicates that air pollution contributes to cardiopulmonary mortality. There is ongoing debate regarding the size and shape of the pollution-mortality exposure-response relationship. There are also growing appeals for estimates of pollution-mortality relationships that use public data and are based on large, representative study cohorts. Objectives: Evaluate fine particulate matter air pollution (PM2.5) and mortality using a large cohort that is representative of the U.S. population and is based on public data. Additional objectives include exploring model sensitivity, evaluating relative effects across selected subgroups, and assessing the shape of the PM2.5-mortality relationship. Methods: National Health Interview Surveys (1986-2014), with mortality linkage through 2015, were used to create a cohort of 1,599,329 U.S. adults and a sub-cohort with information on smoking and BMI of 635,539 adults. Data were linked with modeled ambient PM2.5 at census tracts. Cox Proportional Hazards models estimated PM2.5-mortality hazard ratios for all-cause and specific causes of death controlling for individual risk factors and regional and urban versus rural differences. Sensitivity and subgroup analyses were conducted and the shape of the PM2.5-mortality relationship was explored. Results: Estimated mortality hazard ratios, per 10 µg/m3 long-term exposure to PM2.5, were 1.12 (95% CI=1.08–1.15) for all-cause mortality, 1.23 (1.17–1.29) for cardiopulmonary mortality, and 1.12 (1.00 – 1.26) for lung cancer mortality. In general, PM2.5-mortality associations were consistently positive for all-cause and cardiopulmonary across key modeling choices and across sub-groups of sex, age, race-ethnicity, income, education levels, and geographic regions. Discussion: This large, nationwide, representative cohort of U.S. adults provides robust evidence that long-term PM2.5 exposure contributes to cardiopulmonary mortality risk. The ubiquitous and involuntary nature of exposures and the broadly observed effects across sub-populations underscore the public-health importance of breathing clean air.