The aim of the study was to report the outcome of treatment of 97 dogs with lymphoma that received a multi-agent chemotherapy protocol containing epirubicin as the primary anthracycline. Seventy-five dogs received a 25-week protocol with no maintenance phase whilst 22 dogs received a maintenance phase. Complete response rate was 96% and time to first relapse (TTR) and overall survival (OS) time for all dogs were 216 and 342 days, respectively. Dogs with T-cell lymphoma and those classified as WHO substage b had significantly poorer OS times and TTR. The protocol was well tolerated with toxicity similar to doxorubicin-containing protocols. Epirubicin as part of a multi-agent protocol is safe and effective in the treatment of canine multicentric lymphoma. There is a high initial response rate and an overall median survival time that is similar to other published doxorubicin-containing protocols.