OBJECTIVES: To describe a chemotherapy protocol combining lomustine and doxorubicin in canine histiocytic sarcoma, including outcomes and toxicity. MATERIALS AND METHODS: Retrospective review of case records for dogs with histiocytic sarcoma treated with lomustine and doxorubicin (± cyclophosphamide) alternating every 2 weeks. Data collected included signalment, clinical signs, clinicopathological abnormalities, extent of disease, response, toxicity, time to tumour progression and survival time. RESULTS: Of 17 dogs, 15 had disseminated or metastatic disease. The median number of chemotherapy cycles (one dose of each drug) received was three; most dogs discontinued therapy due to progressive disease. Dose reductions or delays occurred in 18% of cycles. The overall response rate was 58%, with a median time to tumour progression of 185 (range, 59 to 268) days for responders. The overall median survival time was 185 (18 to 402) days. No significant prognostic factors were identified. CLINICAL SIGNIFICANCE: The protocol appeared well-tolerated, had some efficacy against canine histiocytic sarcoma in the study population and could be considered as an alternative to single-agent protocols; prospective comparison may be warranted.