A 1.5 kg, male, wild-caught tiger rat snake (Spilotes pullatus) presented with an externally visible distension of the body wall at the level of the heart. Ultrasound examination showed marked pericardial effusion. Pericardial fluid showed no bacterial or fungal growth, few leukocytes, and few suspected reactive mesothelial or neoplastic cells. Therapeutic pericardiocentesis was successfully performed, removing most of the fluid from the pericardial sac. The snake had mild lethargy and weakness immediately after the procedure but returned to normal behavior within 2 wk. Repeat pericardiocentesis was performed 6 mo after the initial presentation when moderate refilling of the pericardial sac was seen. The snake died 4 days after the second procedure with acute hemorrhage. Pericardial mesothelioma was diagnosed by histopathology after postmortem examination. This report provides the first documented case of mesothelioma in a tiger rat snake and the first description of the disease in colubrids.