Male rats were injected daily ip (350 mg/100 g body weight) with L-arginine from 1 to 4 weeks. Weekly changes were assessed by glucose tolerance, pancreatic insulin, histology, immunohistochemistry, ultrastructure, and quantification of insulin mRNA by in situ hybridization. Following Week 1, light microscopy revealed areas of focal acinar cell degeneration and incipient disaggregation of exocrine cytoarchitecture. Ultrastructural changes revealed initial attenuation in endoplasmic reticulum and condensation and clumping of nuclear chromatin. Some mitochondria appeared swollen and the plasma membrane showed areas of focal disintegration. Islets appeared normal, although pancreatic insulin levels were lower than controls as was the quantified signal for insulin mRNA. At the end of Week 2, acinar necrosis was evident throughout most pancreatic lobules. Increasing numbers of acinar cells underwent progressive degeneration with further loss of plasma membrane integrity, the appearance of autophagic vacuoles, increased cytoplasmic debris, and mitochondrial disruption. At Week 4, only isolated single acinar cells remained within a fibrous connective tissue matrix contiguous with ducts, blood vessels, intrapancreatic nerves, and islets. Immunohistochemistry of islets and nerves revealed normal endocrine and neural components. Although nonfasted, arginine-treated rats were normoglycemic and no further significant changes in pancreatic insulin and mRNA were found between Weeks 2 and 4, some impairment of glucose tolerance was present throughout the 4-week period. Data support the hypothesis that excess arginine selectively destroys acinar cells. It is suggested that necrosis arises from attenuation in nucleoprotein synthesis which may result from amino acid imbalance and/or toxicity. Excess arginine-treated animals may serve as a model for the study of acute and chronic pancreatitis.