Systemic toxicity of intravenously delivered chemotherapy is a limiting factor in the treatment of many cancers. We have shown that intratumoral injection of antineoplastic drugs can provide high localized drug concentrations with greatly reduced systemic toxicity. Using albumin microspheres as a drug carrier, localized and sustained release of chemotherapeutic drugs has been achieved by intratumoral injection, thus increasing the intratumoral dose and antitumor efficacy. Microspheres provide the advantages of localized, prolonged drug release. The efficacy and toxicity of intratumoral free mitoxantrone or mitoxantrone-loaded albumin microspheres were evaluated in a murine breast cancer model. In the same model, a combination of these two therapies was also evaluated. Results indicated that intratumoral mitoxantrone, especially in microsphere preparations, significantly improved survival and decreased systemic toxicity.