The Metropolitan Region of Santiago has been declared as nonattainment area for carbon monoxide (CO). The data was based on seven air monitoring stations that do not necessarily represent the real population exposure. Usually, a series of coefficients that relates the concentration of pollutants with health effects (betas of the concentration-response equations) are used. For the calculation of these betas, normally, a city average air pollution concentration is used; nevertheless, these betas do not necessarily represent the real risk of exposure that the inhabitants are experimented. For this reason, this study estimates two aspects that are unknown and that are necessary to policymakers in public health decisions. First, estimate the exposure at a lower spatial resolution level and, second, estimate a concentration-response curve that differs spatially and depends on the proportion of susceptible groups. We followed the Air Pollution and Health, European Approach/Spanish Multicenter Study on the Relationship Between Air Pollution and the Mortality methodology for the determination of the short-term health effect due to CO population exposure at the three spatial levels (city, zone, and county). We found that there are different risks in cardiorespiratory mortality in the group over 64 years old associated to an unequal exposure to CO in Santiago city. The higher risks are in counties located to the south-east of the city. These finding confirm the necessity to face, in a different way, the approach when evaluating control strategies and policy decision to control air pollution in Santiago.