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Objective To assess the burden of diseases and quality of life (QOL) of patients for a large variety of diseases within general practice. Design In a representative nationwide cross-sectional study, a total of 825 general practitioners (GPs) were randomly selected from across France. Independent investigators recruited 8559 patients attending the GPs' practices. Data on QOL (12-Item Short Form questionnaire) and other individual characteristics were documented by the independent investigators for all participants in the waiting room. Medical information was recorded by GPs. Sampling was calibrated to national standards using the CALMAR (CALage sur MARges) weighting procedure. Associations of lower scores (ie, below vs above the first quartile) of physical and mental component scores (physical component summary score (PCS) and mental component summary score (MCS), respectively) with main diseases and patients characteristics were estimated using multivariate logistic regression. Weighted morbidity rates, PCS and MCS were computed for 100 diagnoses using the International Classification of Diseases (9th version). Results Overall mental impairment was observed among patients in primary care with an average MCS of 41.5 (SD 8.6), ranging from 33.0 for depressive disorders to 45.3 for patients exhibiting fractures or sprains. Musculoskeletal diseases were found to have the most pronounced effect on impaired physical health (OR=2.31; 95% CI 2.08 to 2.57) with the lowest PCS (45.6 (SD 8.8)) and ranked first (29.0%) among main diagnoses experienced by patients followed by cardiovascular diseases (26.7%) and psychological disorders (22.0%). When combining both prevalence and QOL, musculoskeletal diseases represented the heaviest burden in general practice. Conclusions Etude épidémiologique de l'Impact de santé public sur 3 groupes de pathologies (EPI3) is the first study to provide reference figures for burden of disease in general practice across a wide range of morbidities, particularly valuable for health-economics and healthcare-system evaluation., Article summary Article focus The impact of diseases on quality of life (QOL) in general practice has been assessed among selected samples of patients, usually from studies including a limited number of medical practices and/or focusing mainly on chronic conditions. There is a clear need for more data on QOL of patients in primary care; the aim of the Etude épidémiologique de l'Impact de santé public sur 3 groupes de pathologies (EPI3) survey was to provide reference figures for disease burden in this setting. Key messages The EPI3 study was a cross-sectional survey combining unique data from patients and general practitioners (GPs), and allowed provision of reference figures for the vast majority of diseases encountered in primary care for a large number of patients. The study highlighted the burden of musculoskeletal and psychological disorders, experienced by more than half the patients. Although social and medical determinants of patients' QOL were somewhat similar than those found in previous studies in primary care, the EPI3 survey showed more pronounced mental impairment in French patients. Strengths and limitations of this study No nationwide study on burden of disease combining both prevalence measures and QOL assessment has been conducted to date, addressing such a large variety of diseases in general practice. On-site selection and recruitment by an independent investigator limited the possibility of selection bias among patients, and the participation of physicians added high specificity to medical data collection. A study design providing a high specificity in data collection led to a relatively low response rate from GPs. However, stratified recruitment phases and sample sizes from both GPs and patients highly representative of national standards ensured the strong external validity of the results. Home consultations, which are common among GPs in France, were not surveyed which could have led to an underestimation of the burden of disease.