HTLV-I is an endemic retrovirus responsible for the adult T-cell leukemia/lymphoma (ATLL). This aggressive lymphoid proliferation is associated with a bad prognosis due to the resistance of HTLV-I-infected cells to most classical chemotherapeutic agents. Here we review recent advances in ATLL immunotherapy. We particularly focus on promising data from our group, characterizing a new mouse monoclonal antibody (mAb A24) against the human transferrin receptor (TfR-1). Monoclonal antibodies to target cell differentiation markers on ATLL cells have already been proposed as therapeutic agents. However, in clinical trials acute forms of ATLL were resistant to these immunotherapies. A24 binds TfR-1 (K(d) 2.7 nM) and competes with transferrin for receptor binding. It blocks the proliferation of malignant cells (TfR-1(high)), such as HTLV-I-infected T cells but not of resting cells. A24 induces TfR-1 endocytosis in lysosomal compartments where the receptor is degraded leading to intracellular iron deprivation. In HTLV-I-infected cells, A24 targets and induces apoptosis of both chronic and acute ATLL forms, independent of antibody aggregation, antibody-dependent cellular cytotoxicity and/or complement addition. The antibody efficacy was confirmed in animal models. We are currently developing strategies to use A24 in clinical trials.