This study examines the human health implications of natural ventilation in California office buildings. We modeled work-time exposures using field data on indoor and outdoor ozone and particulate matter from four case studies in naturally ventilated offices and published data from mechanically ventilated offices. We also modeled the amount of time that windows would be open in the naturally ventilated office and used the results to estimate the difference in pollutant exposures for occupants of naturally ventilated versus mechanically ventilated, air-conditioned offices. Based on published concentration–response equations, we estimated the incremental changes in health outcomes that resulted from the difference in exposures for occupants in the two types of offices. We also estimated the differences in sick building symptom rates based on symptom prevalence rates in naturally ventilated and air-conditioned offices. Finally, we developed first-order estimates of the health-related costs and benefits of retrofitting 10 percent of California's current office space to use natural ventilation. Findings included an increase in annual health-related costs from increased exposure to ozone and particulate matter of between $130 million and $207 million, and a reduction in sick building syndrome symptom costs, valued between $4.3 million and $11.5 million. Our estimates have a high degree of uncertainty and exclude potentially significant health-related costs and benefits of both naturally ventilated and air-conditioned buildings. Nonetheless, these estimates indicate that health-related costs of natural ventilation are significant and warrant further study. We also explore several mitigation options that could limit the health and economic impacts of natural ventilation.