Air pollution is an important health risk concern and an economic burden, notably on low- and middle-income countries. The aim of this study was to determine the mortality burden of cardiovascular and respiratory diseases, specifically, the relative risk due to air pollution and the economic valuation derived from life-years lost within the population of São Paulo, Brazil. This study was conducted using a retrospective Health Impact Assessment (HIA) approach via daily time series of cardiovascular and respiratory deaths for the population of São Paulo from 2000 to 2011. The effects of particulate matter smaller than 10 µm (PM10) were estimated with Poisson generalized additive models. The single-day lag effects of air pollutant exposure were estimated for 0–3-day lags. Therefore, we obtained the years of life lost (YLL) through the disability-adjusted life years (DALY) method to estimate the burden of disease due to air pollution in São Paulo. The value of a life year (VOLY) was then applied to convert the YLL component to economic loss. The results showed an association between PM10 and cardiovascular and respiratory mortality, lagging 3 days. The YLL totaled 231,691.8 years, meaning an overall economic loss of more than US$14.1 billion. In conclusion, knowledge regarding the costs of premature deaths related to air pollution can be used to improve public policy and to facilitate decision making in the context of scarce resources.