Background: General practitioners (GPs) play a crucial role in the fight against the COVID-19 pandemic as the first point of contact for possibly infected patients and are responsible for short and long-term follow-up care of the majority of COVID-19 patients. Nonetheless, they experience many barriers to fulfilling this role. The PRICOV-19 study investigates how GP practices in 38 countries are organized during the COVID-19 pandemic to guarantee safe, effective, patient-centered, and equitable care. Also, the shift in roles and tasks and the wellbeing of staff members is researched. Finally, PRICOV-19 aims to study the association with practice- and health care system characteristics. It is expected that both characteristics of the GP practice and health care system features are associated with how GP practices can cope with these challenges. Methods: Using a cross-sectional design, data are collected through an online questionnaire sent to GP practices in 37 European countries and Israel. The questionnaire is developed in multiple phases, including a pilot study in Belgium. The final version includes 53 items divided into six sections: patient flow (including appointments, triage, and management for routine care); infection prevention; information processing; communication; collaboration and self-care; and practice and participant characteristics. Between 13 and 636 GP practices per country participated in the study resulting in a sample of 4,786 GP practices in total. Questionnaire data are linked with OECD and HSMR data regarding national policy responses to the pandemic and analyzed using multilevel models considering the system- and practice-level. Discussion: To the best of our knowledge, the PRICOV-19 study is the largest and most comprehensive study that examines how GP practices function during the COVID-19 pandemic. Its results can significantly contribute to better preparedness of primary health care systems across Europe for future major outbreaks of infectious diseases.