The effects of iron overload on pancreatic iron content and morphology were investigated. Sprague-Dawley rats were randomized into an iron-overloaded group, which received a single subcutaneous injection of 1.2 g/kg elemental iron as iron-dextran complex, and placebo-treated pair-fed controls. Animals were studied after a 10-month observation period. Tissue nonheme iron content was measured, and histologic examination was carried out. Chronic iron-overloaded animals showed significant increases in tissue iron content. There was a statistically significant increase in stainable iron in perivascular, parenchymal, and lymphoid tissue in the iron-overloaded group. Although pancreatic fibrosis was present in the iron-overload group, it was not statistically significant. The iron-overloaded animals showed some islet cell destruction. In contrast, no significant islet cell destruction was seen in the control group. However, the difference was not statistically significant. Moreover, the serum glucose levels were the same in both groups, suggesting that there was no significant impairment of pancreatic endocrine function. Thus, chronic experimental iron overload in rats leads to significant increases in tissue iron content, but no significant morphologic alterations of the pancreas with the dose and route of iron administered in this animal model.