We have investigated the stability of doxorubicin and daunorubicin complexes with Fe(3+) in aqueous solution. Doxorubicin and daunorubicin are anthracycline chemotherapeutic agents that differ structurally by the presence of a hydroxymethylketone functionality in doxorubicin versus a methyl ketone moiety in daunorubicin. We demonstrate that the presence of the hydroxyl group in doxorubicin enhances its 1:1 complexation with Fe(3+) relative to that seen for daunorubicin. We utilize UV-visible absorbance, circular dichroism, fluorescence and EPR spectroscopies, molecular dynamics, and semiempirical calculations to understand how the presence of an additional hydroxyl group affects the interactions of anthracyclines with Fe(3+). Our data indicate that the binding mode of iron in the complex is different for doxorubicin and daunorubicin.