The goals of this retrospective study were to determine the patient characteristics of dogs with high-grade primary mediastinal lymphoma and to determine outcome and associated prognostic factors. A total of 42 dogs were identified, in which 36 received treatment and had follow-up information available. The most common clinical signs included lethargy, anorexia and polyuria/polydipsia. Hypercalcemia and pleural effusion were common findings at diagnosis. The phenotype was almost exclusively T-cell, most often in association with lymphoblastic cytomorphology as defined by the World Health Organization (WHO) lymphoma classification scheme. The overall progression-free survival (PFS) and overall survival (OS) were 133 and 183 days, respectively. Treatment with a CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) protocol was associated with an improved PFS (144 days) and OS (194 days) when compared with dogs that received other medical therapies (P = .005 and P = .002, respectively); the absence of pleural effusion at diagnosis was associated with an increased OS but not PFS. These results suggest that while the prognosis for dogs with mediastinal lymphoma is poor, survival may be improved with treatment using a CHOP-based protocol.