Epirubicin (EPI) has strong cytotoxic activity that makes it a potential candidate for the treatment of malignant gliomas. To minimize toxicity and increase CNS penetration, EPI was incorporated into biodegradable polymers, and its in vitro and in vivo properties were studied. 9L, F98, C6, U251, and EMT-6 cell lines were treated with EPI in vitro and cell viability was measured. Toxicity of EPI/polycarboxyphenoxypropane-sebacic-acid (pCPP:SA) polymers was tested in vivo using F344 rats intracranially implanted with EPI polymers (2-50% by weight). The efficacy of 50% EPI:pCPP:SA polymers was determined in F344 rats intracranially challenged with 9L and treated either simultaneously or 5 days after tumor implantation. The efficacy of 50% EPI:pCCP:SA polymers administered on Day 5 in combination with oral TMZ was determined in rats intracranially challenged with 9L gliosarcoma. EPI was cytotoxic in all cell lines used in vitro. Intracranial implantation of the EPI polymers in rats generated neither local nor systemic toxicity. Animals receiving intracranial EPI on Day 5 had 50% long-term survivors (LTS), which was superior to local EPI delivered on Day 0 (LTS = 12.5%). Animals receiving intracranial EPI in combination with oral TMZ had 75% LTS whereas no other group had LTS. In those EPI treated animals that died before the controls there was evidence of intracranial hemorrhage. Systemic epirubicin resulted in high toxicity levels and early deaths in all the experiments. EPI polymers, alone or in combination with oral TMZ, is an effective therapeutic modality against experimental 9L gliosarcoma.