The nephrotoxic potential of anti-inflammatory drugs alone and in compound preparations has been known for over fifty years. Nephrotoxicity associated with selective cyclooxygenase 2 (COX-2) inhibitor use is reported in adult patients but not in children. We present here the first report of reversible acute renal failure associated with the COX-2 inhibitor rofecoxib (Vioxx) in three children. Patient 1, an 18 month old girl with neonatal Bartter syndrome, developed acute renal failure with a peak creatinine of 1.9 mg/dl (164 micromol/l) and severe hyperkalemic metabolic acidosis. Patient 2, a 14 year old boy with a history of rheumatic fever, developed acute renal failure with a peak creatinine of 2.7 mg/dl (240 micromol/l). While patient 3, a healthy 14 year old girl, developed acute renal failure and tubulointerstitial nephritis confirmed on renal biopsy with a peak creatinine of 3.3 mg/dl (287 micromol/L). All children had been taking non-selective non-steroidal anti-inflammatory drugs (NSAID's) immediately prior to rofecoxib use. Renal function returned to normal within one week in all three patients and has remained normal at follow-up. This paper highlights the nephrotoxic risk of COX-2 inhibitor use in the pediatric population.