The therapeutic response and toxic effects of chemotherapy using several doses of doxorubicin in conventional solution form or bound to an Ion-exchange resin were compared in a rat tumor model, to assess the relationship of drug dose to therapeutic efficacy and associated toxicity. Single bolus injections of 3.0, 4.5, 6.0, 7.5 and 9.0 mg/kg were administered via the abdominal aorta to rats bearing hindlimb tumors. Tumor size was measured serially and the growth rates of treated groups were compared with a control growth curve. In addition, the effect of empty microspheres on tumor growth rate was assessed. The levels of circulating white blood cells were measured and compared to control levels to provide an indication of the severity of bone marrow toxicity experienced by each form of treatment. Finally, any difference in the distribution of doxorubicin to tumor, hindlimb and cardiac tissue following administration of doxorubicin as free drug or on microspheres was ascertained. Empty Ion-exchange resin exerted a small although significant detrimental effect on tumor growth which may be explained by the embolization of microspheres in the precapillary blood vessels of the tumor resulting in a transient delay in tumor growth rate. The lowest dose of doxorubicin produced a significantly better therapeutic response when administered in the free drug form, but higher doses elicited an equivalent delay in tumor growth for both drug microsphere and free drug groups in a dose-dependent manner, with the maximum anti-tumor response occurring at the highest dose. Treatment with free doxorubicin at high doses resulted in significant reductions of circulating white blood cells suggesting the occurrence of bone marrow toxicity. However, addition of Ion-exchange microspheres evinced no significant change in white cell count. Consistently higher levels of doxorubicin were present in the normal hindlimb and tumor tissue of microsphere treated animals over a period of 96 h, indicating prolonged release of drug from the microsphere matrix. Conversely, there was a reduction in the amount of doxorubicin present in cardiac tissue of drug microsphere treated animals compared to free drug treated animals shortly after treatment. In summary, the administration of doxorubicin on Ion-exchange microspheres reduced bone marrow toxicity without altering cytotoxic function and demonstrated the potential of microspheres in the prevention of long-term cardiac toxicity.