Calcium oxalate crystals are not encountered in normal animal tissues, except for the human thyroid, where they were found in 79 of 100 routine consecutive autopsies. They appear during childhood, and numbers of crystals increase with age. In diffuse hyperplasia, prevalence was higher, but crystals were fewer than expected. In adenomas and carcinomas, crystals were decreased except for three cases with a striking focal increase. None was found in 22 adult primate thyroids. After Clorox® digestion of human thyroids, calcium oxalate dihydrate was identified by x-ray diffraction and infrared spectroscopy. Origin, tissue and species localization are discussed in relation to ascorbate metabolism, thyroperoxidase, and calcitonin. Possible metabolic roles are suggested. Calcium oxalate crystals injected in animals and humans initiate a foreign body reaction with giant cells. In Hashimoto’s thyroiditis, crystals disappear but occasionally remain with giant cell reaction. In subacute thyroiditis, granulomas are related more to colloid than to crystals.