A 14-yr-old male Nile lechwe (Kobus megaceros) from the Jackson Zoo (Mississippi, USA) had chronic weight loss that was associated with elevated serum alkaline phosphatase levels. Approximately 4 yr after the first clinical signs of weight loss, the animal fractured its left rear femur and was subsequently euthanized; on the same day necropsy was performed. The liver was grossly enlarged and contained a smooth-surfaced nodular mass that occupied the majority of the right lobe of the liver. The mass had a liver-like appearance exhibiting a tan–red coloration but having a soft consistency. A single, approximately 0.6 cm, round, slightly elevated discrete red nodule was present in the left anterior lung. Microscopically, the hepatic mass and pulmonary nodule diffusely consisted of irregular cords of cells exhibiting hepatoid features, but containing no evidence of normal portal bile duct or portal triad development. To our knowledge, this is the first report in the scientific literature of a naturally occurring case of hepatocellular carcinoma in a Nile lechwe or in any antelope species.