Pancreaticopleural fistula is an uncommon clinical condition. Its presentation is often confusing because of the paucity of clues suggestive of pancreatic disease and the preponderance of pulmonary symptoms and signs. Most patients are alcoholics but only one-half will have a clinical history of previous pancreatitis. Pleural effusions are large, recurrent, and highly exudative in nature. Many patients go through extensive pulmonary evaluation before the pancreas is identified as the site of primary pathology. An elevated serum amylase may be the first clue to the diagnosis. However, the key to the diagnosis is a dramatically elevated pleural fluid amylase. Effusions in association with acute pancreatitis, esophageal perforation, and thoracic malignancy are important to consider in the differential diagnosis of an elevated pleural fluid amylase but are usually easy to exclude. Computed tomography is excellent in defining pancreatic abnormalities and should be the first abdominal imaging study in suspected cases. Endoscopic retrograde cholangiopancreatography (ERCP) is used as a diagnostic tool only in confusing cases. Although no systematic study evaluates medical versus surgical therapy, we recommend an initial 2 to 4-week trial of medical therapy, including allowance of no oral intake, total parenteral nutrition, chest tube thoracostomy, and possibly a regimen of somatostatin or its analogs. The major complication in these patients is superinfection, which results in significant morbidity and mortality. Failure of medical therapy should be considered failure of pleural effusion(s) to clear, recurrence after reinstatement of oral intake, or superinfection. For those patients who fail to benefit from medical therapy, surgery is indicated.(ABSTRACT TRUNCATED AT 250 WORDS)