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SummaryBackground Cases of severe drug hypersensitivity, demonstrating a variable spectrum of cutaneous and systemic involvement, are reported under various names, especially drug reaction with eosinophilia and systemic symptoms (DRESS). Case definition and overlap with other severe cutaneous adverse reactions (SCAR) are debated. Objectives To analyse the spectrum of signs and symptoms of DRESS and distribution of causative drugs in a large multicentre series. Results The male/female ratio was 0Á80; females were borderline significantly younger than males. Next to the ubiquitous exanthema, the main features were eosinophilia (95%), visceral involvement (91%), high fever (90%), atypical lymphocytes (67%), mild mucosal involvement (56%) and lymphadenopathy (54%). The reaction was protracted in all but two patients; two patients died during the acute phase. Drug causality was plausible in 88% of cases. Antiepileptic drugs were involved in 35%, allopurinol in 18%, antimicrobial sulfonamides and dapsone in 12% and other antibiotics in 11%. The median time interval after drug intake was 22 days (interquartile range 17-31) for all drugs with (very) probable causality, with differences between drugs. Conclusion This prospective observational study supports the hypothesis that DRESS is an original phenotype among SCAR in terms of clinical and biological characteristics, causative drugs, and time relation. The diversity of causative drugs was rather limited, and mortality was lower than that suggested by prior publications.