Background <p>The prognosis with canine multicentric T-cell lymphoma is guarded. Alkylator-based protocols such as LOPP (lomustine, vincristine, procarbazine, prednisone) and MOPP (mechlorethamine, vincristine, procarbazine, prednisone) have been evaluated as the primary treatment for naïve canine T-cell lymphoma. This study compared response, outcome, and prognostic data in dogs treated with MOPP or LOPP in naïve T-cell lymphoma.</p> Methods <p>This multi-institutional, retrospective study included dogs with naïve multicentric, intermediate to large cell, T-cell lymphoma. Dogs with T-zone lymphoma, gastrointestinal, or cutaneous involvement were excluded. Complete response (CR) rate, overall response rate (ORR), progression-free survival (PFS), and overall survival time (OST) were evaluated. Prognostic factors influencing outcome data were evaluated.</p> Results <p>Seventy-one dogs were included. CR rate was significantly higher in dogs treated with LOPP compared to MOPP (86% vs. 65%, <i>p</i> = 0.003). The median PFS was significantly longer in dogs treated with LOPP versus MOPP (208 days vs. 102 days, <i>p</i> = 0.018). The median OST was not significantly different between protocols (298 days vs. 231 days, <i>p</i> = 0.318). The frequency of adverse events was similar between groups. Remission was more likely in dogs with a cranial mediastinal mass or CD4⁺CD8⁻ immunophenotype. The presence of a cranial mediastinal mass, any response to chemotherapy or achievement of a CR positively impacted PFS. Achievement of a CR positively impacted MST.</p> Conclusions <p>This study supports the use of alkylator-rich multi-drug chemotherapy protocols for naïve multicentric T-cell lymphoma. LOPP has a higher likelihood of CR and longer PFS compared to MOPP. While the prognosis with T-cell lymphoma remains guarded with an MST of 8–9 months, 25% of dogs treated with alkylator-rich protocols experienced a prolonged survival of 16 months.</p>