Time-series analyses have shown that ozone is associated with increased risk of premature mortality, but little is known about how O3 affects health at low concentrations. A critical scientific and policy question is whether a threshold level exists below which O3 does not adversely affect mortality. We developed and applied several statistical models to data on air pollution, weather, and mortality for 98 U.S. urban communities for the period 1987–2000 to estimate the exposure–response curve for tropospheric O3 and risk of mortality and to evaluate whether a “safe” threshold level exists. Methods included a linear approach and subset, threshold, and spline models. All results indicate that any threshold would exist at very low concentrations, far below current U.S. and international regulations and nearing background levels. For example, under a scenario in which the U.S. Environmental Protection Agency’s 8-hr regulation is met every day in each community, there was still a 0.30% increase in mortality per 10-ppb increase in the average of the same and previous days’ O3 levels (95% posterior interval, 0.15–0.45%). Our findings indicate that even low levels of tropospheric O3 are associated with increased risk of premature mortality. Interventions to further reduce O3pollution would benefit public health, even in regions that meet current regulatory standards and guidelines.