Oxygen-derived free radicals play an important role in the pathogenesis of experimental acute pancreatitis in the isolated perfused canine pancreas. We have previously found that pretreatment with allopurinol inhibits xanthine oxidase--apparently the primary source of free radical generation in this model--and prevents the initial development of pancreatitis. In these experiments, we evaluated whether allopurinol administered after the onset of pancreatitis would arrest the progression of the disease process. Edema formation, weight gain, and the release of amylase activity into the perfusate in the ex vivo perfused canine pancreas model were monitored during a 4-hour perfusion period. There were six experimental groups: Group I (control) received no treatment, group II (allopurinol alone) received only allopurinol (100 mg) at the start of perfusion, and groups III through VI were each given an infusion of 0.3 ml of oleic acid (FFA) over a 1-hour period to initiate acute pancreatitis. Group III (FFA alone) received no other treatment. In group IV (pretreatment with allopurinol), group V (concurrent treatment with allopurinol), and group VI (posttreatment with allopurinol), allopurinol (100 mg) was administered 1 hour before, concurrent with, or at the end of the FFA infusion, respectively. Pretreatment with allopurinol prevented edema formation, markedly attenuated weight gain, and the release of amylase caused by the FFA infusion. Administration of allopurinol concurrent with the FFA infusion provided only partial protection, whereas posttreatment with allopurinol failed to arrest the progression of the injury process. Therefore, the use of allopurinol to inhibit oxygen-derived free radical production from xanthine oxidase prevented the development of acute pancreatitis in this model; however, treatment with allopurinol after initiation of the disease process failed to arrest the progression of acute pancreatitis.