Abstract The cell surface glycoprotein CD38 is highly expressed on the surface of several B cell lineage cancers, such as the plasma cell malignancy multiple myeloma, some lymphomas and chronic lymphocytic leukemia (CLL), where it is a marker of unfavorable prognosis. CD38 is a transmembrane receptor and ectoenzyme that is absent or expressed at a low level on most resting leukocytes under normal conditions, making this an appealing target for directed therapy for hematological malignancies. Recent clinical trials with antibodies to CD38 have shown promise in multiple myeloma. While these antibodies rely on the recruitment of an immune response for cytotoxicity, we have developed an engineered toxin body (ETB) comprising a CD38 binding scFv and a modified Shiga-like Toxin A subunit capable of specifically recognizing and directly killing CD38 expressing cells. The CD38 targeted ETB has a different mechanism of action than current treatments for multiple myeloma (such as immunomodulatory agents, protease inhibitors and chemotherapies). Our CD38 targeted ETB has shown to be well tolerated in mice and displays dose dependent efficacy in a CD38 positive tumor setting. The CD38 targeted ETB significantly reduced tumor burden and increased survival over a 40-fold dose range in a disseminated Daudi xenograft, early treatment model. In this setting, the mean tumor burden at day 28 was reduced to 29% of control for the lowest dose group (0.05 mg/kg) and less than 1% of control for the two higher doses (0.5 and 2 mg/kg). Median survival of the control, untreated group was 34 days; the low dose group had extended median survival to 59.5 days and, at the day 60 study end, 90 or 100% of mice were alive in the higher two dosing groups. Our results show that the CD38 targeted ETB is a promising targeted therapeutic agent against CD38 positive cancer cells and is currently under further development. Citation Format: Garrett L. Robinson, Sangeetha Rajagopalan, Brigitte Brieschke, Jennifer Erdman, Jane Neill, Rodney Flores, Julia Foree, William Null, Jensing Liu, Jack P. Higgins, Erin K. Willert. In vivo efficacy of a CD38-specific engineered toxin body. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr A15.