Rats received up to four subcutaneous injections of caerulein (20 microg/kg) in hourly intervals to induce a mild edematous pancreatitis. A single dose of caerulein resulted in significant oxidative modification of proteins in pancreatic homogenates as compared to saline-injected controls (p < 0.01). Repeated injections of the secretagogue were unable to induce a further increase in modified proteins. Protein oxidation preceded the formation of the lipid peroxidation product malondialdehyde as well as edema and the increase in serum amylase by 1-2.5 h. Western blotting for oxidatively modified proteins confirmed the results of the quantitative measurements and did not reveal individual, selectively modified proteins. These findings indicate that oxidative stress and oxidative protein modification are very early events in the initial period of caerulein pancreatitis. This may explain the poor success rate of most studies that administered antioxidants therapeutically during or after initiation of pancreatitis.