BACKGROUND: The mental health and well-being of GPs is a critical issue as they play a vital role in providing healthcare services to individuals and communities. Research has shown that GPs often face high levels of stress, burnout, and mental health problems due to their demanding work environment. During the COVID-19 pandemic, GPs faced additional challenges which further impacted their mental health and well-being. This study aims to investigate the impact of systemic work-related stressors on the level of well-being of GPs in Belgium during the pandemic, with a particular emphasis on identifying regional variations between Flanders, Wallonia, and Brussels-Capital. METHODS: Data were collected with a self-reported online questionnaire from 479 GPs Belgian practices between December 2020 and August 2021 as part of the international PRICOV-19 study that explored the organization of general practices during COVID-19 in 38 countries to guarantee safe, effective, patient-centered, and equitable care. Well-being was evaluated by the Mayo Clinic's expanded 9-item well-being index. RESULTS: The findings of this study reveal notable regional discrepancies in the degree of well-being experienced by Belgian GPs, with the Walloon region displaying the lowest level of well-being (37%) in a population highly susceptible to professional distress (57%). Among the key stressors contributing to such distress, financial difficulties among patients (p < 0.011), the fee-for-service payment system (p = 0.013), a lack of work-related purpose (p = 0.047), and inadequate work-life balance (p < 0.001) were identified as significant factors. When examining the influence of regional disparities, it was found that the sole significant interaction between work-related stressors and region regarding the probability of experiencing distress was related to the possibility of workload sharing among practice personnel. CONCLUSION: The findings from this study underscore the imperative for more comprehensive research aimed at ...