Chronic lymphocytic leukemia (CLL), the most common type of leukemia in adults, is characterized by the progression of malignant CD5⁺ B lymphocytes in the peripheral blood, bone marrow and secondary lymphoid organs. CLL cells express CD1d and can be recognized by iNKT cells in vitro; however, the interaction between iNKT and CLL cells in the natural history of the disease is unknown. We addressed the issue by: 1. investigating CD1d expression on CLL cells and autologous circulating iNKT cells in 72 patients undergoing routine follow up; 2. assessing CLL progression in the presence or absence of iNKT cells in the Tcl1 transgenic mouse model. Patient analysis revealed an inverse correlation between CD1d expression by CLL cells and autologous iNKT cell counts. HighCD1d expression by CLL cells and low iNKT cell counts correlated with disease progression. Residual iNKT cells from CD1d^highCLL patients (progressive) were also markedly hypo-responsive ex vivo, whereas those from CD1d^low CLL patients (stable) were fully functional. In multivariate analysis including also the classic CLL prognostic factors (RAI, ZAP-70, Chromosomal aberrations, IGVH mutations, CD38) iNKT cell counts and CD38 expression by leukemic cells were the only independent parameters that predicted leukemia progression. In Tcl1 mice, the lack of iNKT cells (Tcl1-Jα18KO, Tcl1-CD1dKO) resulted in a significantly faster CLL onset and progression, compared to TCL1-WT animals. Tcl1 iNKT cells decreased and became functionally impaired upon disease progression, consistent with the high CD1d expression by mouse CLL cells. Altogether, these results strongly support a role for iNKT cells in the immunesurveillance of CLL and highlight iNKT cell counts as new prognostic disease marker.