BACKGROUND Ibuprofen is a commonly used non-steroidal anti-inflammatory drug. While the vast majority of exposures to the drug do not result in significant morbidity, we are reporting 2 fatalities that resulted from massive ibuprofen ingestion. CASE 1: A 17-year-old girl presented to the emergency department (ED) following an ibuprofen overdose; she was unresponsive with a metabolic acidosis and hypothermic. Her serum ibuprofen concentration was 352 microg/mL: the therapeutic range is 10-50 microg/mL. Despite intensive supportive care and continuous veno-venous hemofiltration, she expired. CASE 2: A 49-year-old man presents to the ED with a history of divalproex sodium and ibuprofen ingestion. He was unresponsive, hypotensive, and had a significant metabolic acidosis. His serum ibuprofen concentration was 260 microg/mL and serum valproate concentration was 560 microg/mL: the therapeutic range is 50-100 microg/mL. In spite of supportive care and hemodialysis, he expired. CONCLUSIONS We will describe 2 cases of ibuprofen overdose characterized by cardiovascular collapse, acidosis, and hypothermia despite the use of vasopressors and renal replacement therapy. Although rarely reported, massive ibuprofen overdose may result in refractory multisystem organ failure and death.