Direct experimental proof has been sought for the hypothesis that liposomal drugs targeted against internalizing epitopes (e.g., CD19) will have higher therapeutic efficacies than those targeted against noninternalizing epitopes (e.g., CD20). Anti-CD19-targeted liposomes were rapidly internalized into human B-lymphoma (Namalwa) cells, whereas those targeted with anti-CD20 were not internalized. Similar in vitro binding and cytotoxicity were observed for anti-CD19-targeted and anti-CD20-targeted liposomal formulations of doxorubicin (DXR). Therapeutic experiments were performed in severe combined immunodeficient mice inoculated i.v. with Namalwa cells. Administration of single i.v. doses of DXR-loaded anti-CD19-targeted liposomes resulted in significantly greater survival times than either DXR-loaded anti-CD20-targeted liposomes or nontargeted liposomes. The therapeutic advantage of targeting internalizing versus noninternalizing epitopes has been directly demonstrated.