Background: Longitudinal studies indicate strong associations between school proficiency and indicators of mental health throughout adulthood, but the mechanisms of such associations are not fully elucidated. The Kupol study is a prospective cohort study in Sweden set up in order to: (i) describe the association of school pedagogic and social environment and its specific dimensions with the risk of mental ill-health and psychiatric disorders in adolescence; (ii) evaluate the direct effects of school pedagogic and social environment on mental health and the effects mediated by the individual’s academic achievements; and (iii) assess if school pedagogic and social environment are associated with mental ill-health through epigenetic mechanisms, in particular those involving genes regulating the response to stress. Methods: The Kupol cohort at baseline consists of 3959 children attending the 7th grade of compulsory school (13-14 years old) in 8 regions of central Sweden in the school years 2013-2014 or 2014-2015. Three follow-up surveys in subsequent years are planned. Teachers’ and students’ perceptions of the culture, climate and ethos of their schools, and students’ mental ill-health are assessed at the whole school level by annual questionnaire surveys. In order to conduct epigenetic analyses saliva specimens are collected from a nested sample of students at inception and two years later. Further, class-, family- and child-level information is collected at baseline and during each year of follow-up. Self-reported information is being complemented with register data via record-linkages to national and regional health and administrative registers. Discussion: The topic being investigated is new, and the sample constitutes the largest adolescent cohort in Sweden involved in an ad hoc study. Epigenetic analyses centered on environmental cues to stress response are a thoroughly new approach. Finally a notable feature is the multi-informant and multi-method data collection, with surveys at the school, class, family, and student level. Collaboration and data access: interested investigators should contact the coordinating centre. Additional information is available on the study’s website, http://kupolstudien.se/ .