Background: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe multi-organ drug hypersensitivity reaction (DHR) involving T cells. DRESS patients have a heightened risk (~25%) of developing multiple drug hypersensitivity (MDH) to unrelated drugs from the first reaction. This project aims to characterise DRESS, focusing on those with and without MDH, to identify potential biomarkers for further drug reactions. Methods: This multicentre cross-sectional study analysed clinical features and immune responses, including T cell activation and in vitro cytokine secretion using Cyto-LTT. The study included 20 DRESS patients (12 with MDH), 8 maculopapular exanthema (MPE) patients (4 with MDH), and a control group of 9 healthy donors (HD). Clinical assessments included detailed histories, skin testing, and the RegiSCAR score for diagnosing DRESS. Results: The Cyto-LTT improved diagnostic sensitivity, particularly in DRESS patients, identifying 19% of drugs that were negative by skin testing. MDH patients’ leukocytes exhibited stronger and broader secretions of cytokines and cytotoxic mediators, up to ten-fold higher compared to DHR patients with a single drug sensitisation. T cells from recovered delayed DHR patients exhibited signs of chronic activation after resolution, with elevated CD69 and PD-1 but reduced CD38 and OX-40 levels compared to HD. Conclusion: Recovered delayed DHR patients display an altered T cell activation profile suggesting a “chronic disease” state, possibly explaining the heightened risk of MDH. Increased cytokine secretions, such as stimulation index > 10, especially for cytotoxic mediators, may differentiate those at risk for MDH.