Abstract Purpose: Targeted therapeutics are a goal of medicine. Methods for targeting T-cell lymphoma lack specificity for the malignant cell, leading to elimination of healthy cells. The T-cell receptor (TCR) is designed for antigen recognition. T-cell malignancies expand from a single clone which expresses one of 48 TCR variable beta (Vβ) genes, providing a distinct therapeutic target. We hypothesized that a monoclonal antibody that is exclusive to a specific Vβ would eliminate the malignant clone while having minimal effects on healthy T-cells. Experimental Design: We identified a patient with large granular T-cell leukemia, and sequenced his circulating T-cell population, 95% of which expressed Vβ13.3. We developed a panel of anti-Vβ13.3 antibodies to test for binding and elimination of the malignant T-cell clone. Results: Therapeutic antibody candidates bound the malignant clone with high affinity. Antibodies killed engineered cell lines expressing the patient TCR Vβ13.3 by antibody-dependent cellular cytotoxicity, TCR-mediated activation-induced cell death, and exhibited specific killing of patient malignant T-cells in combination with exogenous NK cells. EL4 cells expressing the patient’s TCR Vβ13.3 were also killed by antibody administration in an in vivo murine model. Conclusions: This approach serves as an outline for development of therapeutics that can treat clonal T-cell based malignancies and potentially other T-cell-mediated diseases.