As part of an ongoing effort to develop a clinically acceptable doxorubicin formulation, targeted against B-cell malignancies, this study compared long-circulating (Stealth) immunoliposomes (SIL) that were targeted against the B-cell antigen CD19, via a whole HD37 monoclonal antibody (HD37 mAb), versus its Fab' fragment (HD37 Fab') or an HD37-c-myc-Cys-His5 single chain Fv fragment (scFv, HD37-CCH) directed against the same epitope. Compared to untargeted liposomes (SL), SIL showed increased binding in vitro to CD19-expressing Raji cells and, when loaded with doxorubicin (SIL-DXR), increased cytotoxicity against Raji (CD19(+)), but not Molt4 (CD19(-)) cells. Pharmacokinetics and biodistribution studies using dual-labeled liposomes (lipid and drug) in naive and Raji-bearing mice showed that SIL-DXR targeted via HD37 Fab' exhibited the same long circulation half-life as SL-DXR. SIL-DXR targeted via HD37-CCH was cleared faster than SL-DXR due to increased liver uptake, which was related to the poly-His and/or the c-myc tags in the scFv construct. SIL-DXR targeted via HD37 mAb was cleared rapidly from circulation due to Fc-mediated uptake in the liver and spleen. All three formulations of SIL-DXR extended the mean survival time of Raji-bearing mice compared to SL-DXR or free DXR. SIL-DXR targeted via HD37 Fab', which had the longest circulation half-life, appeared to be slightly more effective in prolonging survival times than SIL-DXR targeted via either HD37-CCH or HD37 mAb.