A 9-year-old female crossbred dog was presented to the Hospital Universitario Veterinario Rof Codina (Universidad de Santiago de Compostela, Lugo, Spain) for acute onset of severe, progressive swelling of the head, neck, and cranial trunk. Survey radiographs and ultrasonography revealed a large, heterogeneous mass in the cranial mediastinum, compressing or growing into a large blood vessel within the cranial mediastinum and displacing the heart dorsocaudally. At postmortem examination, the mass was diagnosed as a large, localized mesothelioma. Localized mesotheliomas are rare neoplasms in dogs but should be considered as a possible differential diagnosis for cranial vena cava syndrome. The anatomic distribution and clinical features of mesothelioma in the present report are similar to other cases in humans.