We have developed a guinea pig model of iron overload toxicity. Animals were administered intraperitoneal iron dextran 3 times a week to achieve total body iron load of 0.25, 0.5, 1.0, 1.5, and 2.0 g Fe/kg body weight in less than 30 days. Quantitation of tissue iron levels with atomic absorption indicated increased iron deposition in liver and heart of the iron-loaded guinea pigs (p < 0.001). Additionally, the iron-loaded pigs demonstrated decreased nuclear magnetic resonance spectroscopy T1 relaxation times in both liver and heart (p < 0.001). Serum iron, total body iron capacity, and transferrin saturation values were also determined in guinea pigs treated with 0.25, 0.5, and 1.0 g Fe/kg body weight. Serum iron and total iron-binding capacity were significantly increased at 0.5 and 1.0 g Fe/kg; transferrin saturation was elevated at 0.25 and 1.0 g Fe/kg. kg. Histologic examination of liver, heart, and bone marrow as well as ultrastructural studies on liver and heart confirmed increased iron deposition in treated animals. At the low iron dose level of 0.5 g Fe/kg, liver iron particles were primarily confined to Kupffer cells with minimal hepatocellular localization. Increased hepatocellular iron deposition was observed with larger doses of loaded iron. Myocardial iron was most prominent in interstitial cells of the epicardium, endocardium, myocardium, and coronary adipose tissue. Ultrastructurally, the presence of iron particles in perinuclear, membrane-bound structures (consistent with lysosomes) was confirmed using x-ray microanalysis. These morphological studies suggest that in this animal model siderosis of hepatic mononuclear phagocyte and myocardial interstitial cells may be the initial lesions leading to further biochemical and functional abnormalities. Correlation between tissue iron measurements and both light and electron microscopic changes, presented in this report, serve to introduce the iron-loaded guinea pig as a model for the study of iron-induced tissue damage.