This study examines the long-term effects of ozone exposure on mortality in a large U.S. cohort. Data from the American Cancer Society Cancer Prevention Study II (CPS II) were analyzed with air pollution data from 96 metropolitan statistical areas. The study included 448,850 participants followed for 18 years, with 118,777 deaths recorded. Daily ozone concentrations (April–September, 1977–2000) and fine particulate matter (PM2.5) concentrations (1999–2000) were used to assess their association with mortality. In single-pollutant models, both PM2.5 and ozone were significantly associated with increased risk of death from cardiopulmonary causes. In two-pollutant models, PM2.5 was linked to cardiovascular deaths, while ozone was associated with respiratory deaths. A 10 ppb increase in ozone concentration was linked to a 4% increase in respiratory mortality risk. The association between ozone and respiratory mortality was not affected by confounding variables or statistical models. The study found that ozone had no significant effect on cardiovascular mortality when PM2.5 was considered, but it did show a significant effect on respiratory mortality. Previous studies have shown mixed results regarding ozone's impact on mortality, with some suggesting no significant effect and others indicating a possible link to respiratory issues. The study controlled for individual and ecological risk factors, including age, sex, race, smoking, and socioeconomic variables. Ozone and PM2.5 concentrations were measured at various monitoring sites, and their associations with mortality were analyzed using Cox regression models. The results suggest that long-term ozone exposure is independently associated with increased respiratory mortality, but not with cardiovascular mortality. The study highlights the need for further research to clarify the mechanisms and long-term effects of ozone exposure on health. The findings underscore the importance of considering ozone as a risk factor for respiratory diseases, particularly in areas with high ozone concentrations.This study examines the long-term effects of ozone exposure on mortality in a large U.S. cohort. Data from the American Cancer Society Cancer Prevention Study II (CPS II) were analyzed with air pollution data from 96 metropolitan statistical areas. The study included 448,850 participants followed for 18 years, with 118,777 deaths recorded. Daily ozone concentrations (April–September, 1977–2000) and fine particulate matter (PM2.5) concentrations (1999–2000) were used to assess their association with mortality. In single-pollutant models, both PM2.5 and ozone were significantly associated with increased risk of death from cardiopulmonary causes. In two-pollutant models, PM2.5 was linked to cardiovascular deaths, while ozone was associated with respiratory deaths. A 10 ppb increase in ozone concentration was linked to a 4% increase in respiratory mortality risk. The association between ozone and respiratory mortality was not affected by confounding variables or statistical models. The study found that ozone had no significant effect on cardiovascular mortality when PM2.5 was considered, but it did show a significant effect on respiratory mortality. Previous studies have shown mixed results regarding ozone's impact on mortality, with some suggesting no significant effect and others indicating a possible link to respiratory issues. The study controlled for individual and ecological risk factors, including age, sex, race, smoking, and socioeconomic variables. Ozone and PM2.5 concentrations were measured at various monitoring sites, and their associations with mortality were analyzed using Cox regression models. The results suggest that long-term ozone exposure is independently associated with increased respiratory mortality, but not with cardiovascular mortality. The study highlights the need for further research to clarify the mechanisms and long-term effects of ozone exposure on health. The findings underscore the importance of considering ozone as a risk factor for respiratory diseases, particularly in areas with high ozone concentrations.