An adult male Savannah monitor (Varanus exanthematicus) was evaluated for lethargy, anorexia, and coelomic distension. Ultrasonographic investigation identified both pericardial and coelomic effusion. Clinical laboratory investigations and radiographs did not identify a definitive disease process, and culture of the coelomic fluid was negative for bacterial growth. A tentative diagnosis of neoplasia, with mesothelioma as a potential type, was made after cytological examination of the coelomic fluid and echocardiography. Surgical exploration and excisional biopsy of the pericardium for drainage of the fluid and determination of a final diagnosis was carried out. The lizard died 16 h post-anesthesia. Histopathology confirmed changes throughout the coelomic cavity consistent with a diagnosis of mesothelioma. Mesothelioma is a rarely reported neoplasm in all animals but particularly in reptiles. This case report provides a detailed clinical and pathologic description of the lesions associated with mesothelioma in a monitor lizard. In addition, this is the first known report of a surgical pericardectomy in a reptile.