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Background: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare but potentially fatal drug hypersensitivity reaction. Objective: To explore treatment approaches across Europe and their impact on the disease course, as well as prognostic factors and culprit drugs. Methods: In this retrospective European multicentric study, we included patients with probable or certain DRESS (RegiSCAR score≥4) between January 2016 and December 2020. Independent associations between clinical parameters and the risk of intensive care unit admission and mortality at three months were assessed using a multivariable-adjusted logistic regression model. Results: A total of 141 patients from 8 tertiary centres were included. Morbilliform exanthem was the most frequent cutaneous manifestation (78.0%). The mean af)fected body surface area (BSA) was 67%, 42% of the patients presented with erythro)derma, and 24.8% had mucosal involvement. Based on systemic involvement, 31.9% of the patients had a severe DRESS. Anticonvulsants (24.1%) and sulphonamides (22.0%) were the most frequent causative agents. In all, 73% of the patients were treated with systemic glucocorticoids, and 25.5% received topical corticosteroids as monotherapy. Few patients received antiviral drugs or anti-IL5. No patients re)ceived intravenous immunoglobulins. The overall mortality was 7.1%. Independent predictors of mortality were older age (≥57.0 years; fully adjusted OR, 9.80; 95% CI, 1.20–79.93; p = 0.033), kidney involvement (fully adjusted OR, 4.70; 95% CI, 1.00– 24.12; p = 0.049), and admission in intensive care unit (fully adjusted OR, 8.12; 95% CI, 1.90–34.67; p = 0.005). Relapse of DRESS and delayed autoimmune sequelae oc)curred in 8.5% and 12.1% of patients, respectively. Conclusions: This study underlines the need for diagnostic and prognostic scores/ markers as well as for prospective clinical trials of drugs with the potential to reduce mortality and complications of DRESS. [ABSTRACT FROM AUTHOR]