We examined the association of long-term, daily 1-h maximum O₃ (ozone) exposures on cause-specific mortality for 22.2 million US Medicare beneficiaries between 2000–2008. We modeled the association between O₃ and mortality using age-gender-race stratified log-linear regression models, adjusted for state of residence. We examined confounding by (1) adjusting for PM_2.5 (particles with aerodynamic diameters <2.5 μm) and NO₂ (nitrogen dioxide) exposures, temperature, and neighborhood-level characteristics and behaviors, and (2) decomposing O₃ into its temporal and spatio-temporal components and comparing estimated risk ratios. We also examined sensitivity of our results to alternate exposure measures based on warm-season 8-h daily maximum and 24-h average exposures. We found increased risks from long-term O₃ exposures to be strongest and most consistent for mortality from respiratory disease (1.030, 95% CI: 1.027, 1.034) (including COPD (chronic obstructive pulmonary disease)), CHF (congestive heart failure), and lung cancer (1.015, 95% CI: 1.010, 1.020), with no evidence of confounding by PM_2.5, NO₂, and temperature and with results similar across O₃ exposure measures. While significant, associations between long-term O₃ exposures and CVD (cardiovascular)-related mortality (1.005, 95% CI: 1.003, 1.007) were confounded by PM_2.5 and varied with the exposure measure, with associations no longer significantly positive when warm-season 8-h maximum or 24-h average O₃ was used to assess exposures. In this large study, we provide strong evidence that O₃ exposure is associated with mortality from respiratory-related causes and for the first-time, lung cancer, but raise questions regarding O₃-related impacts on CVD mortality. Our findings demonstrate the need to further identify potential confounders.