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Introduction: Personal lifestyle and air pollution are potential risk factors for major non-communicable diseases (NCDs). However, these risk factors have experienced dramatic changes in the Beijing-Tianjin-Hebei (BTH) region in recent years, and few cohorts have focused on identifying risk factors for major NCDs in this specific region. The current study is a large, prospective, long-term, population-based cohort study that investigated environmental and genetic determinants of NCDs in BTH areas. The results of this study may provide scientific support for efforts to develop health recommendations for personalized prevention. Methods: About 36,000 participants 18 years or older would be obtained by multistage, stratified cluster sampling from five cities for the baseline assessment. Participants underwent seven examinations primarily targeting respiratory and circulatory system function and filled out questionnaires regarding lifestyle behavior, pollutant exposure, medical and family history, medication history, and psychological factors. Biochemistry indicators and inflammation markers were tested, and a biobank was established. Participants will be followed up every 2 years. Genetic determinants of NCDs will be demonstrated by using multiomics, and risk prediction models will be constructed using machine learning methods based on a multitude of environmental exposure, examination data, biomarkers, and psychosocial and behavioral assessments. Significant spatial and temporal differentiation is well-suited to demonstrating the health determinants of NCDs in the BTH region, which may facilitate public health strategies with respect to disease prevention and survivorship-related aspects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Cao, Guo, Pan, Cui, Sun, Zhao, Han, Zhang, Wang, Niu, Tang, Shan and Zhang.)