Background: Toxic epidermal necrolysis (TEN) is a rare but life-threatening complication that may occur in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT), particularly in the context of extensive drug exposure. In this population, TEN can closely resemble severe acute graft-versus-host disease (GVHD), making diagnosis and management challenging. Case presentation: We report the clinical course of an allo-HSCT recipient who developed a rapidly progressive skin rash early after transplantation, and we analyzed the clinical features, histopathology, treatment and outcome. Results: The patient developed rapidly progressive epidermal detachment with severe oral, ocular, and genital mucosal involvement shortly after exposure to trimethoprim/sulfamethoxazole (TMP-SMX). Disease severity was reflected by a SCORTEN score of 5, corresponding to a very high predicted mortality risk. The clinical picture raised concern for both TEN and severe acute GVHD, while histopathological findings favored TEN but were not definitive. Management included systemic corticosteroids, intravenous immunoglobulin, ruxolitinib, and intensive supportive care. The patient gradually re-epithelialized and recovered without long-term sequelae. Conclusions: This case underscores the diagnostic difficulty of distinguishing TEN from severe acute GVHD in the early post-transplant period. Careful assessment of drug exposure, clinical evolution, and multidisciplinary evaluation are essential to guide timely and appropriate management.