Introduction: Drug reaction with eosinophilia and systemic symptoms (DRESS) and secondary hemophagocytic lymphohistiocytosis (sHLH) are life-threatening disorders that share several clinical and paraclinical characteristics. We herein describe a girl with DRESS caused by trimethoprim-sulfamethoxazole with sHLH as a complication. Case presentation: A 13-year-old girl presented with a recurrent UTI due to Escherichia coli, and was treated with trimethoprim-sulfamethoxazole, which caused two generalized rash at her 8 and 12 years. Three days later, she developed generalized rash, fatigue, and a reduced appetite with a fever of 39.7°C, followed by facial edema, painful cervical lymphadenopathy, abdominal pain, and diarrhea, subsequently became incoherent and developed seizures. She was admitted in a hemodynamically unstable condition with a morbilliform exanthema on 90% of her body surface, with cervical and retroauricular lymphadenopathy, hepatomegaly, and generalized tonic-clonic seizures. Viral infections were rule out as well as mycoplasma. Autoantibodies were negative and complement was normal. Brain magnetic resonance imaging with contrast and angioresonance showed no abnormalities. The patient was admitted to the intensive care unit because of multiple organ failure with suspected DRESS and a RegiSCAR score of 7. A bone marrow aspirate was performed because of the unusual presentation, with evidence of hemophagocytic cells; thus, the criteria for HLH were satisfied. Intravenous immunoglobulin and methylprednisolone were started, with clinical improvement. Discussion: Drug-specific T cells in DRESS are a result of cross-reactivity with previously sensitized effector memory T cells after infection, an exaggerated immune response occurs after a viral reactivation or a simultaneous infection in association with concomitant administration of a drug. In this case, the UTI associated with more than 8 days of exposure to the offending drug probably induced massive activation of T cells that promoted the production of proinflammatory cytokines, generating macrophage activation. Cases of DRESS and sHLH in pediatric patients reported share several clinical and paraclinical characteristics, and they overlap with other pathologies such as Kawasaki disease, multisystem inflammatory syndrome in children, and systemic-onset juvenile idiopathic arthritis. Conclusion: The co-occurrence of DRESS and sHLH is rare, serious, and life-threatening. Early diagnosis and timely treatment are required to reduce patient morbidity and mortality.