An adult female great plated lizard, Gerrhosaurus major, presented with anorexia, weight loss, dehydration, and central nervous system signs. After four weeks of unsuccessful therapy, the lizard was humanely euthanized. Gross pathologic examination revealed a large, granular, soft tissue mass compressing the brain. The mass was diagnosed histologically as a ventricular cholesterol granuloma. Cholesterol granulomas were also present within the fat pad and ovary. The plasma cholesterol level in this plated lizard was elevated and was likely a predisposing factor. Intracranial cholesterol granuloma should be a differential for central nervous system signs in adult female reptiles, particularly those with concomitant hypercholesterolemia.