BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare and severe hypersensitivity reaction triggered by medications, characterized by fever, rash, eosinophilia, and multi-organ involvement. While DRESS shares features with Stevens-Johnson syndrome (SJS) and fixed-drug eruption, distinguishing factors such as organ involvement, absence of mucosal lesions, and extended latency periods complicate its diagnosis. This case report aims to highlight an unusual presentation of DRESS to contribute to the growing understanding of its diagnostic and management challenges. CASE REPORT We present the case of a 25-year-old woman with DRESS attributed to trimethoprim-sulfamethoxazole (TMP-SMX) for acute pyelonephritis. Symptoms, including fever, diffuse maculopapular rash, facial edema, and lymphadenopathy, began within 6 days of drug exposure, deviating significantly from the typical 2- to 8-week latency period. Differential diagnoses, such as Stevens-Johnson syndrome and fixed-drug eruption, delayed the recognition of DRESS. A calculated RegiSCAR score of 5 indicated a probable case. Management included discontinuation of TMP-SMX, initiation of systemic corticosteroids, and supportive care. The patient experienced rapid symptom resolution without relapse, demonstrating a favorable outcome despite atypical features. CONCLUSIONS This case underscores the diagnostic complexities of DRESS, particularly in distinguishing it from other severe cutaneous drug reactions and managing atypical presentations with multiple drug exposures. It emphasizes the importance of early identification, timely cessation of the offending agent, and individualized treatment strategies. Further investigation into the role of concurrent antibiotic use in accelerating DRESS onset and exacerbating severity is warranted to enhance clinical understanding and improve patient outcomes.