Functional and morphological changes in hepatocytes, indicating induction of the drug metabolizing enzymes and free radical-mediated damage, were found in 4 patients with idiopathic chronic pancreatitis. The possibility that reflux of abnormal bile (rich in lipid peroxidation and other products generated through hepatic metabolism of xenobiotics) into the pancreatic duct may initiate pancreatic damage was negated when bile duct ligation and bile diversion did not abolish attacks of pancreatitis in 3 cases, although the evidence of reflux was indisputable in 1 of them who also had a pancreatoduodenectomy. Pancreatic acinar cells from that patient showed extensive microvesiculation, as did hepatocytes from each case. These observations suggest that pancreatic and liver damage in chronic pancreatitis proceed independently but by the same mechanism-heightened, but unmitigated, oxidative detoxification of xenobiotics by cytochromes P450. Therefore, although bile reflux is not a prerequisite, it could compound injury in the head of the gland. Antioxidants were prescribed to the 3 cases mentioned and, from the outset, to a fourth patient who showed the same liver changes. This unconventional approach has held attacks at bay during a follow-up period of 5 yr.