Metastatic mineralization was diagnosed in 16 captive two-toed sloths ranging in age from 2-mo to 26-yr-old (mean 11.9 yr) and housed at facilities throughout the United States. Gross and histological lesions were characterized as well as concurrent disease processes. Gross mineralization was detectable at necropsy in 5 of 16 sloths, and was most prominent in the great vessels and particularly the aorta. Affected vessels were diffusely dilated, firm and brittle with tan plaques that partially occluded the lumen. Histologically, vascular mineralization was detected in 9 of 16 sloths and varied from moderate to severe including osseous metaplasia, smooth muscle hyperplasia and degeneration consistent with arteriosclerosis. Mineralization was detected throughout viscera, most commonly in the stomach mucosa (13 of 16 sloths), kidneys (12 of 16 sloths) and lungs (6 of 15 sloths), and was associated with mononuclear inflammation and local tissue destruction. Fourteen of 16 sloths had significant renal disease, including 2 which were treated for clinical renal failure prior to death. Nine of 12 had mild to severe cardiomyopathy, possibly secondary to severe vascular compromise. Metastatic mineralization is caused by prolonged hypercalcemia. Common causes include high calcium diets, dietary or metabolic calcium: phosphorus imbalance, hypervitaminosis D, and primary or secondary hyperparathyroidism. Severe vascular mineralization occurred in sloths in the absence of renal disease.