We describe the first severe systemic hypersensitivity reaction to ibuprofen in a pediatric patient with previously undiagnosed systemic lupus erythematosus (SLE). An 11-year-old Thai male presented with fever, rash, altered mental status, and hypotension after oral administration of ibuprofen leading to the diagnosis of SLE. Re-dosing with ibuprofen resulted in recurrence of presenting symptoms. Severe hypersensitivity with hypotension can be a rare consequence of the use of ibuprofen in children with collagen vascular disease. When encountered in an otherwise healthy child, a high index of suspicion must be maintained for the diagnosis of SLE.