Safety and efficacy of pegylated liposome encapsulated doxorubicin (PL-DOX) was compared with free doxorubicin as an adjuvant monotherapy in dogs with splenic haemangiosarcoma after splenectomy in a randomized prospective clinical trial. A total of 17 dogs in each group were treated. No significant difference in survival between the two treatments was found. The calculated median overall survival time for the 34 dogs was 166 days [95% confidence interval (CI) 148–184]. The ½ year and one-year survival was 41.2% (95% CI 24.8–56.9) and 22.7% (95% CI 9.9–37.4), respectively. In dogs treated with PL-DOX, a desquamating dermatitis like palmar-plantar erythrodysesthesia (PPES) was seen in two dogs, while three other dogs showed anaphylactic reactions. Cardiotoxicity was not seen in either treatment groups.