The systematic case-referent method is a special case-referent design originally developed for pharmacoepidemiologic research purposes. It consists in the systematic collection of series of incident cases of various disorders and the assembling of a general reference pool, from which “controls” are secondarily selected to be matched to specific cases. Both series are collected independently from each other and with no a priori hypothesis to be investigated. The reference pool can be either general or limited to a subpopulation, representative of the source population of the cases. Based on clinical recruitment of cases and referents, the design allows a very high specificity of diagnosis and documentation of clinical variables. All cases and referents are systematically documented on all treatments received before the incidence of the cases or before identification of referents. This documentation is done preferentially using objective sources assembled independently (linkage to claims data, medical records, pharmacy records, prescription records, hospital discharge letters). It can be completed with patients’ interviews using standardised research tools, in particular for over-the-counter drug use and self-medication, and for the documentation of adherence to treatment and specific time-windows of exposure. Likewise, all cases and all referents are systematically documented on a series of risk factors, which are common to most epidemiological studies and are not hypothesis-dependent. Whenever the documentation of a confounding factor specific to the disease at hand is necessary, additional questionnaires can be applied to all or a sample of patients. The method has been successfully implemented for the pharmacoepidemiologic study of myocardial infarction, stroke, lupus, multiple sclerosis, rheumatoid arthritis, Guillain Barré syndrome, idiopathic thrombocytopenic purpura, type 1 diabetes mellitus, suicide attempts, breast cancer, and other disorders, for the analysis of the risk or preventing action of NSAIDs, statins, antiplatelet agents, anticoagulants, insulins, vaccines and other drugs.