In order to identify CT signs that could be used to distinguish cranial mediastinal lymphoma and thymic epithelial neoplasia, a retrospective case-control study was done. Associations between CT signs and diagnosis were tested using binary logistic regression and results expressed as odds ratio and 95% confidence interval. Sixty-two dogs that had thoracic CT and confirmed diagnosis of lymphoma (n = 33) or thymic neoplasia (n = 29) were sampled. Thymic neoplasms included 24 thymomas and five thymic carcinomas. Dogs with thymic epithelial neoplasia were significantly older than dogs with lymphoma (median age 8.6 years versus 6.0 years, P = .007), but there were no significant differences in prevalence of clinical signs. Diagnosis of thymic epithelial neoplasia was associated with heterogeneous attenuation in pre- (odds ratio 23.3, 95% confidence interval, 4.5-121.1) and post-contrast (odds ratio 30.7, 95% confidence interval, 3.6-265.0) images. Conversely, envelopment of the cranial vena cava by the mass was less likely with thymic epithelial neoplasia than lymphoma (odds ratio 0.07, 95% confidence interval, 0.007-0.66). Greater standard deviation of Hounsfield unit values in post-contrast images was associated with thymic epithelial neoplasia (P = .005). Based on ROC analysis, SD > 17HU of the mass in post-contrast images had a sensitivity of 72% and specificity of 79% for thymic epithelial neoplasia. There were no significant differences in morphology, prevalence of calcification, mediastinal lymphadenopathy, cranial vena cava invasion, collateral vessels, or pleural fluid associated with these tumors. Thymic epithelial neoplasms tended to occur in older dogs and were heterogeneous in CT images, whereas mediastinal lymphoma was more homogeneous and more likely to envelop the cranial vena cava.