The effect of inhibitors of prostaglandin synthesis on diuretic action was examined in patients with ascites due to chronic liver disease and in normal subjects. In patients with ascites, natriuresis after 80 mg i.v. furosemide was reduced 82% by pretreatment with indomethacin. Creatinine clearance was reduced only 16%. These effects were likely due to inhibition of renal prostaglandin synthesis, since urinary prostaglandin E2 fell and there was also reduction in natriuresis with naproxen (52%). The effects were not specific for furosemide since spironolactone-induced natriuresis was also reduced by indomethacin (82%), naproxen (52%), and aspirin (33%). In normal subjects, indomethacin reduced furosemide natriuresis by only 14% while creatinine clearance was not affected. The mechanisms of these drug interactions are uncertain but probably involve renal hemodynamics which appear to be supported importantly by renal prostaglandins in patients with ascites due to liver disease.