Due to the early spread of this tumor, chemotherapy is frequently recommended in addition to other treatments. The only exception to this is when the tumor is localized to the very uppermost layer of the skin. Then surgical removal of the tumor may be all that is required.

The most commonly used chemotherapy drug is doxorubicin. This drug is administered intravenously once every three weeks. Dogs handle this drug well and the risk of serious side effects is low, between 5 to 10 percent. Potential side effects include gastrointestinal problems, including nausea, vomiting, diarrhea or loss of appetite, and a drop in the white blood cell count, leaving a pet susceptible to infection. If multiple treatments of this drug are given, cumulative side effects include heart problems. In order to prevent the cumulative side effects, the number of treatments is limited to six or less. In dogs, a heart evaluation (ultrasound and EKG) is recommended prior to giving the drug and before the fifth and sixth treatment.

Other drugs that are used in the treatment of hemangiosarcoma are cyclophosphamide and ifosphamide. Cyclophosphamide is frequently given either with doxorubicin or immediately after. When ifosphamide is used, it is alternated with doxorubicin. Both of these drugs can cause gastrointestinal side effects and a drop in the white blood cell count. In addition, they can cause an irritation in the lining of the bladder causing blood in the urine and straining to urinate. If the drug irritates the bladder the signs will usually resolve in a few days to a few weeks.