Nonsteroidal anti-inflammatory agents are often used to treat acute inflammatory arthritis because of their effectiveness and the infrequency of reported serious side effects. This report describes two patients who had acute intrinsic renal failure that was triggered by indomethacin. Both patients were volume contracted and had other circulatory impairments. Azotemia was so severe as to require temporary hemodialysis in one patient. Intrinsic renal function began to recover within 5 days after discontinuation of indomethacin. At the time that recovery began, urinary prostaglandin excretion increased in both patients. A detailed review of pertinent experimental data indicates that renal production of prostaglandin is an important compensatory response that helps to maintain renal function in the face of diminished renal blood flow. Our cases provide clinical support for this hypothesis and illustrate the fact that indomethacin, by interfering with this protective mechanism, can lead to acute intrinsic renal failure. Clinicians must be aware of this possible complication and use the nonsteroidal anti-inflammatory drugs with caution in patients who have compromised prerenal status.