This study was undertaken to define the earliest ultrastructural changes appearing in the exocrine pancreas and its vasculature during the development of experimental acute pancreatitis induced by the closed duodenal loop technique. Experimental and shamoperated rats were killed at hourly intervals up to 4 hr and at 6 hr postoperatively. Focal acinar cell response included appearance of vacuoles containing uncondensed or partially condensed secretory product, and some rearrangement and dilatation of the rough endoplasmic reticulum within 1 hr. Mild edema was observed and damage to the vascular endothelium developed by 2 hr. At 4 hr focal hemorrhage and a slight inflammatory cell infiltrate was noted which was more prominent at 6 hr. The lack of a correspondence between areas of acinar cell and of vascular abnormalities suggests that factors other than increased secretory back-pressure are involved in the early development of this model of acute pancreatitis.