OBJECTIVES: The EPI3 program aims at evaluating the burden of diseases and quality of life (QOL) of patients seeking care for a large variety of conditions within general practice  METHODS: GPS included 8559 patients attending the practices. Data on QOL (12-Item Short Form questionnaire) and other individual characteristics were documented by the independent investigators for all participants at the waiting room. Medical information was recorded by GPs. Sampling was calibrated to national standards using the CALMAR weighting procedure. Associations of lower scores (i.e., below vs. above the first quartile) of physical and mental component scores (PCS and MCS) with main diseases and patients characteristics were estimated by multivariate logistic regression. Weighted morbidity rates, PCS and MCS were computed for 100 diagnoses using the international classification of diseases (ICD-9, 9th version). RESULTS: Overall mental impairment was observed amongst 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 (2.08–2.57)] with the lowest PCS: 45.6 (SD = 8.8) and ranked first (29.0%) amongst 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: Although social and medical determinants of patients’ QOL were somewhat similar than those found in previous studies in primary care, the EPI3 program showed more pronounced mental impairment in French patients.This 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 health care system evaluation.