Although the postpericardiotomy syndrome is a common complication of cardiac operations, the most effective drug regimen for the treatment of this condition has not been established. The present study was designed to evaluate the effectiveness of nonsteroidal antiinflammatory drugs (NSAIDs) in the treatment of postpericardiotomy syndrome, in a double-blind, placebo-controlled randomized trial with a 10-day course of ibuprofen or indomethacin. Of 1019 adult patients undergoing cardiac operations during a 14-month period, a diagnosis of postpericardiotomy syndrome was made in 187, and 149 were enrolled in the study. Diagnosis was based on the presence of at least two of the following: fever, anterior chest pain, and friction rub. Drug efficacy was defined as the resolution of at least two of these criteria within 48 hours of drug initiation. Ibuprofen and indomethacin were 90.2% and 88.7% effective, respectively, and both were significantly more effective than placebo (62.5%, p = 0.003). The occurrence of side effects, including nausea, vomiting, renal failure, and fluid retention, was low in all groups (13.1% for ibuprofen, 16.1% for indomethacin, and 16.7% for placebo [p = not significant). Length of hospital stay, incidence of ischemic events, and accumulation of significant pericardial effusions were similar in all groups. The results of this study demonstrate that both ibuprofen and indomethacin provide safe and effective symptomatic treatment for postpericardiotomy syndrome.