We aimed to examine the associations of air pollutants and climate change with prevalence of stroke, coronary heart disease (CHD), diabetes (DM) and premature mortality. We used 2010-2013 daily monitoring air pollution data across 200 to 600 counties of 50 U.S. states, and health outcomes data from U.S. EPA and CDC. Six common air pollutant indicators were studied: particulate matters (PM2.5 and PM10), carbon monoxide (CO), nitrogen dioxide (NO), Ozone (O3), sulfur dioxide (SO2), and lead. Monthly, seasonally, and then a 4-yearly average pollutant level was estimated for each county. Air pollution index was weighted by population density. The results show that counties with higher levels of air pollutant indexes had significantly higher prevalence of stroke, CHD, DM and premature death rate (defined as subjects died before 75 years old). After adjustment for county-level socioeconomic status (median household income), these associations remained significant, except for a non-significant association of lead with CHD (0.11, p=0.18) and DM (0.16, p=0.052). Stratification analysis by quartiles of county-level yearly average temperature (F) showed that associations between air pollutants and prevalence of stroke was much stronger (assessed by correlation coefficients) for residents who lived in areas where it had yearly average temperature of 44.3 F (Q1) as compared to those who lived in areas with annual average temperature of 51.2 F (Q2). The corresponding correlation coefficients of PM2.5, PM10, CO, NO, O3, SO2, and lead with stroke rates were 0.55, 0.61, 0.61, 0.64, 0.62, 0.63, 0.49, respectively in residents living in the areas with Q1 temperate, and were 0.43, 0.36, 0.34, 0.32, 0.42, 0.31, and 0.45, respectively in those living in the areas with Q2 temperature. A stronger association between air index and stroke was also observed for residents who lived in an average temperature of 56.7 F (Q3), and 67.7 F (Q4). Similar associations were observed between air pollution and CHD, DM and premature death. In conclusion, using nationally representative datasets the present study provides new evidence of a positive and significant association of air pollution with stroke, CHD, DM and premature death, and these associations are modified by air temperatures.