Cryptosporidiosis, previously unreported in cotton rats (Sigmodon hispidus), was observed in one of nine cotton rats from Pryor, Oklahoma (USA). Infection was confined to the large intestine. Microscopically, numerous cryptosporidians measuring 2 to 3 μm in diameter were intimately associated with the luminal surface of colonic and rectal mucosae. The affected lamina propria of the large intestine was diffusely infiltrated by eosinophils, lymphocytes and macrophages. Ultrastructurally, numerous trophozoites and a single schizont were observed. Microvilli were displaced by the presence of cryptosporidians at the attachment site.