Gallstone pancreatitis is usually related to small stones, which may not be detected by conventional cholecystographic techniques. In the current study, it was hypothesized that some patients with acute pancreatitis of unknown cause could harbor occult microstones in the gallbladder. Therefore, evidence was sought prospectively of missed gallstones by biliary drainage and microscopic examination of centrifuged duodenal bile in 51 patients recovering from an attack of acute pancreatitis, including 24 patients with relapsing episodes. Clusters of cholesterol monohydrate crystals, calcium bilirubinate granules, and/or CaCO3 microspheroliths were found in 67% of the patients. Biliary drainage showed no abnormal findings in 12 patients convalescing from a bout of known alcoholic pancreatitis. Examination of gallbladder bile at cholecystectomy and/or serial ultrasonography of the gallbladder for up to 12 months showed that 73% of the patients with unexplained pancreatitis had biliary sludge or microlithiasis; the prior finding of biliary crystal/solid markers predicted their existence with both a sensitivity and a specificity of 86% and a predictive value of 94%. The probability of harboring occult gallstones was also associated with age (P = 0.004), prior recurrent pancreatitis (P = 0.024), and altered liver function tests results during an index episode (P = 0.003). In 13 patients with cholesterol monohydrate crystals in bile, ursodeoxycholic acid (10 mg.kg-1.day-1) eliminated gallbladder microlithiasis within 3-6 months, and subsequent maintenance treatment with a daily dose of 300 mg prevented both gallstone recurrence and further attacks of pancreatitis over a mean follow-up period of 44 months. Cholecystectomy also prevented gallstone-associated relapses in 17 of 18 patients followed up for a mean postoperative period of 36 months. This study provides firm evidence showing that in most patients with idiopathic acute pancreatitis, the disease is related to microscopic gallstones, as evidenced by the follow-up development of macroscopic stones or sludge and by the prevention of relapses with either cholecystectomy or a cholelitholytic bile acid. Occult gallstones should be strongly suspected when acute pancreatitis of unknown cause occurs in a relapsing manner and in aged patients and when it is associated with altered liver function test results. Biliary microscopy and/or follow-up ultrasonography of the gallbladder provide a simple means of uncovering them to institute appropriate therapy and prevent further attacks.