This retrospective study compares the clinical signs and diagnostic findings of 17 canine patients with histopathological diagnoses of idiopathic pericardial effusion (IPE) or pericardial mesothelioma (MS) in order to identify differences in clinical findings or survival times that might aid in premortem differentiation of these disease conditions. Based on this series of cases, clinical signs, physical examination findings and results of non-invasive diagnostic testing are insufficient to differentiate MS from IPE with confidence unless a discrete pericardial or intrapericardial mass can be identified. Surgical biopsy may be misleading if large amounts of highly reactive and invasive mesothelial cells are seen. Recurrence of significant amounts of pleural effusion within 120 days of pericardiectomy may increase the likelihood that MS is the cause of pericardial effusion in cases in which other causes have been excluded. Survival longer than 120 days postpericardiectomy without chemotherapeutic intervention is associated with a decreased probability of the condition being MS.