Rats maintained on a diet deficient in copper for up to 8-10 weeks exhibit marked necrosis and depletion of acinar cells in the pancreas. When these animals are subsequently fed a copper-supplemented diet, foci of hepatocyte differentiation emerge by about 12 weeks. The present study deals with pancreatic changes during copper depletion and determines the extent of regenerative capacity of the pancreas during the early phases of copper supplementation. During the period of copper depletion, the pancreas gradually decreased in size, and by eight weeks of deficiency weighed approx. 30% as much as the control pancreas. Light-microscopic examination showed focal necrosis of acinar cells at 4 weeks, loss of lobular architecture by six weeks and loss of 85-90% of acinar tissue by eight weeks. Regeneration of the pancreas was initiated by feeding copper-supplemented diet at the end of eight weeks of copper deficiency. The wet weight of the pancreas increased gradually, and by 17 days it weighed 50% more than on the first day of regeneration. Mitotic activity was observed mainly in the acinar cells, beginning at 24 h and reaching a maximum of 19 +/- 1/1000 acinar cells at 72 h, and decreasing steadily thereafter. [3H]Thymidine autoradiography showed a labeling index of 51 +/- 1.7/1000 acinar cell nuclei at 24 h, reaching a peak value of 261 +/- 5.5/1000 acinar cells at 96 h. By 17 days, pancreatic regeneration was only partially complete; however, the proliferative activity was still persistent, albeit at a slower pace. Morphometric analysis of the pancreas on the 17th day of regeneration showed that acinar tissue occupied only 37% of the volume, as compared to 84% in the normal pancreas. These studies clearly demonstrate that acinar tissue of the pancreas following copper deficiency is capable of regeneration, but that the recovery of the pancreas is only partial. Additional studies are necessary to establish the role of this early acinar cell regeneration in pancreatic hepatocyte differentiation.