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PURPOSE Employment is a key social determinant of health. People who are unemployed typically have worse health than those employed. Illness and disability can result in unemployment and be a barrier to regaining employment. We combined a systematic review and knowledge synthesis to identify both studies of employment interventions in health care settings and common characteristics of successful interventions. METHODS We searched the peer-reviewed literature (1995-2017), and titles and abstracts were screened for inclusion and exclusion criteria by 2 independent reviewers. We extracted data on the study setting, participants, intervention, methods, and findings. We also conducted a narrative synthesis and iteratively developed a conceptual model to inform future primary care interventions. RESULTS Of 6,729 unique citations, 88 articles met our criteria. Most articles (89%) focused on people with mental illness. The majority of articles (74%) tested interventions that succeeded in helping participants gain employment. We identified 5 key features of successful interventions: (1) a multidisciplinary team that communicates regularly and collaborates, (2) a comprehensive package of services, (3) one-on-one and tailored components, (4) a holistic view of health and social needs, and (5) prospective engagement with employers. CONCLUSIONS Our findings can inform new interventions that focus on employment as a social determinant of health. Although hiring a dedicated employment specialist may not be feasible for most primary care organizations, pathways using existing resources with links to external agencies can be created. As precarious work becomes more common, helping patients engage in safe and productive employment could improve health, access to health care, and well-being. Key words: social determinants of health; employment; systematic review; work; health care settings; working conditions; chronic disease; vulnerable populations; primary care, INTRODUCTION Employment status is a key social determinant of health. (1,2) Being employed influences our financial security, sense of self, social connections, and social status. Unemployment is associated with worse [...]