Although alcohol abuse is the major cause of chronic pancreatitis, the pathogenesis of alcoholic chronic pancreatitis (ACP) remains obscure. A critical obstacle to understanding the mechanism of ACP is lack of animal models. Our objective was to develop one such model. Rats were pair-fed for 8 weeks ethanol or control Lieber-DeCarli liquid diet. For the last 2 weeks, they received cyclosporin A (CsA; 20 mg/kg once daily) or vehicle. After 1 week on CsA, one episode of acute pancreatitis was induced by 4 x 20 µg/kg injections of cerulein (Cer); controls received saline. Pancreas was analyzed 1 week after the acute pancreatitis. CsA or Cer treatments alone did not result in pancreatic injury in either control (C)- or ethanol (E)-fed rats. We found, however, that alcohol dramatically aggravated pathologic effect of the combined CsA+Cer treatment on pancreas, resulting in massive loss of acinar cells, persistent inflammatory infiltration, and fibrosis. Macrophages were prominent in the inflammatory infiltrate. Compared with control-fed C+CsA+Cer rats, their ethanol-fed E+CsA+Cer counterparts showed marked increases in pancreatic NF-B activation and cytokine/chemokine mRNA expression; collagen and fibronectin; the expression and activities of matrix metalloproteinases 2 and 9; and activation of pancreatic stellate cells. Thus, we have developed a model of alcohol mediated post-acute pancreatitis that reproduces 3 key responses of human ACP: loss of parenchyma, sustained inflammation, and fibrosis. The results indicate that alcohol impairs recovery from acute pancreatitis, suggesting a mechanism by which alcohol sensitizes pancreas to chronic injury.