Paleontological occurrences of helodermatid lizards (Helodermatidae) are relatively uncommon and scattered in the North American fossil record. A recently discovered concentration of vertebrate fossils was exposed in a karstic fissure filling in an active rock quarry in southwestern Oklahoma. Underwater screening of the ancient cave fill yielded numerous isolated and fragmentary skeletal elements of a diversity of small, and a few large, vertebrates including unexpected remains of Heloderma sp. as well as extinct large mammals (horse, peccary, Dwarf Pronghorn), indicating Pleistocene age. Radiometric dating of the locality is not possible because of the leaching, but fossils of the Prairie Vole, Microtus ochrogaster, from the locality help to constrain the age of the deposit between 1.21 Ma and 0.01 Ma. The fossils are the first of Heloderma in the Pleistocene of Oklahoma and the southern Great Plains. Based on taphonomic evidence and the relative abundance of rodent teeth, we infer that the fossils accumulated at least partly as the remains of vertebrates fed upon by Ringtails (Bassariscus; Procyonidae) and other small carnivorous mammals. The Pleistocene occurrence of Heloderma in the southern Great Plains of North American has potential implications for the paleobiogeography of the genus and begs further investigation of fossil herpetofaunas in North America.