Polychlorinated-biphenyls (PCBs) were introduced in the late 1920s and used until the 1970s when they were banned in most countries due to evidence of environmental build-up and possible adverse health effects. However they still persist in the environment, indoors and in humans. Indoor air in contaminated buildings may confer airborne exposure markedly above background regional PCB levels. To date, no epidemiological studies have assessed the health effects from exposure to semi-volatile PCBs in the indoor environment. Indoor air PCBs are generally less chlorinated than PCBs that are absorbed via the diet, or via past occupational exposure; therefore their health effects require separate risk assessment. Two separate cohorts of individuals who have either attended schools (n = 66,769; 26% exposed) or lived in apartment buildings (n = 37,185; 19% exposed), where indoor air PCB concentrations have been measured were created. An individual estimate of long-term airborne PCB exposure was assigned based on measurements. The cohorts will be linked to eight different national data sources on mortality, school records, residential history, socioeconomic status, and chronic disease and reproductive outcomes. The linking of indoor air exposures with health outcomes provides a dataset unprecedented worldwide. We describe a project, called HESPERUS (Health Effects of PCBs in Residences and Schools), which will be the first study of the long term health effects of the lower-chlorinated, semi-volatile PCBs in the indoor environment.