BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe and potentially lethal adverse drug reaction. Its clinical complexity and heterogeneity pose challenges for diagnosis and management. METHODS: We retrospectively reviewed the medical records of patients with DRESS who were admitted to our hospital between 2013 and 2022. Data on demographics, culprit drugs, clinical manifestations, laboratory findings, and treatments were collected. RESULTS: Fifty-one patients were included in the final analysis, with 16 probable and 35 definite cases. The most common causative drugs were antiepileptic drugs (15.7%), anti-tuberculosis drugs (15.7%), and Chinese herbs (9.8%). Common skin manifestations included extensive skin involvement (76.5%), facial edema (66.7%), polymorphic maculopapular lesions (66.7%), and exfoliation (56.9%). Eosinophilia and atypical lymphocytes were noted in 96.1% and 68.6% of the patients, respectively. The liver is the most frequently affected organ. Facial edema, extensive skin involvement, and atypical lymphocytes were correlated with higher Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) scores ( CONCLUSION: Clinical manifestations of DRESS are complex. Facial edema, extensive skin involvement, and atypical lymphocytes have emerged as significant diagnostic indicators.