The CD-19-directed immunotoxin anti-B4-blocked ricin (anti-B4-bR) is currently in clinical trials for the treatment of B-cell malignancies. To explore the potential of using anti-B4-bR with chemotherapy protocols we tested the in vivo efficacy of the immunotoxin in combination with two multi-drug chemotherapeutic regimens in severe combined immunodeficient (SCID) mice bearing disseminated tumors of the multidrug-resistant human B-cell lymphoma Namalwa/mdr-1. In cytotoxicity studies in vitro, combinations of the immunotoxin with cisplatin produced supra-additive killing effects on both Namalwa and Namalwa/mdr-1 cells, whereas anti-B4-bR combined with 4-hydroperoxy- cyclophosphamide caused additive killing of both cell lines. In vivo cyclophosphamide, cisplatin, vincristine, doxorubicin, and etoposide as single agents, were effective in prolonging the survival of SCID mice burdened with the Namalwa tumor, whereas only cyclophosphamide and cisplatin were effective on Namalwa/mdr-1 tumors. Treatment of Namalwa/mdr-1-bearing mice with anti-B4-bR alone or with the drug combination CHOE (consisting of cyclophosphamide, vincristine, doxorubicin, and etoposide) alone increased the lifespan of the tumor- burdened mice by 58% and 73%, respectively. However, treatment with five daily bolus intravenous injections of anti-B4-bR followed by CHOE increased the lifespan by 173%, and 20% of the mice were cured. The drug combination CCE (cyclophosphamide, cisplatin, and etoposide) alone could increase the lifespan of the Namalwa/mdr-1 tumor-burdened mice by 129% compared with untreated controls. Combination therapy with anti-B4- bR and CCE produced long-term cures in 50% of the tumor-burdened mice. These results suggest that anti-B4-bR in combination with current multidrug regimens may constitute a highly efficacious modality for the treatment of drug-resistant B-cell malignancies.