Renal prostaglandins have several key functions in patients with severe liver disease and ascites. Increased activity of vasodilatory prostaglandins counters the underlying impairment in renal perfusion and the effects of vasoactive hormones. Prostaglandins also participate in renin secretion, renal diluting ability, sodium excretion, the action of diuretics, and, possibly, the development of the hepatorenal syndrome. Nonsteroidal anti-inflammatory drugs inhibit these compensatory actions of prostaglandins and cause a functional reduction in glomerular filtration rate and an impairment in sodium and fluid excretion. The severity of these nephrotoxic effects depends on the potency of the drug in inhibiting renal prostaglandins and on patient susceptibility. Patients with ascites and avid sodium retention, sodium-restricted diets, or concurrent diuretic use are most at risk. If nonsteroidal anti-inflammatory drugs must be administered to these patients, the type of drug should be carefully selected and renal function should be closely monitored.