An increasing shortage of skilled personnel, including medical personnel, has been reported in many postindustrial economies. Persisting and growing trends in absenteeism and incapacity to work due to mental disorders are concerning and have increased political, economic, and scientific interest in better understanding and management of determinants related to the work environment and health.This study protocol describes an integrated approach of social research methods to explore determinants of work-related stress in general practice teams as an example for micro, small, and medium-sized enterprises (SMEs).The methods applied will allow an in-depth exploration of work practices and experiences relating to psychological well-being in general practice teams. An ethnographic approach will be used to develop an in-depth understanding of the drivers of work-related stress in general practice teams. We will combine participating observation and individual interviews with five to seven general practitioners (GPs), and five to seven focus group discussions with the nonphysician staff (3-4 participants per group) in approximately four GP group practices and one single practice in Germany. Data collection and analysis will follow a grounded theory approach.The Ethics Committee of the Medical Faculty, University Hospital of Tuebingen, Germany, has approved this study (reference number: 640/2017BO2). Recruitment has commenced with study completion anticipated in mid-2020.The data from this project will be used in follow-up projects to develop and test an intervention to reduce and prevent work-related stress in GP practices and other SMEs.DERR1-10.2196/15809.