gd T cells can display a broad array of anti-tumor functions by combining their rapid innate-like cytotoxic response with secretion of immune-regulatory cytokines, such as IFNg. Intestinal intraepithelial lymphocytes (IELs) are particularly enriched with tissue-resident T gd cells. The present study identify and charaterize for the first time a large subset of human colon-resident T gd IELs expressing the natural cytotoxic receptors (NCRs) NKp46. These NKp46pos Vd1 IELs are gut-specific as we could not find any similar population in several other human compartment such as skin, liver, uterus, cervix or lymph nodes. As expected as tissue-resident lymphocytes, NKp46pos Vd1 IELs mostly carry the Vd1 TCR and are striking different from their NKp46neg circulating that are predominately Vd2 restricted in their TCR. Even though tissue-resident murine T gd cells share several features with human Vd1 cells, we did not find any subset of NKp46pos T gd subset in different anatomical gut sites of BALB/c and C57BL/6 mouse strains. The NKp46pos phenotype reflects a functionally higher anti-tumor potential in vitro compared to their NKp46neg counterpart. Indeed, NKp46pos Vd1 IELs are GranzymeBpos and strongly degranulate and produce IFN-g when co-coltured with K562 leukemia cell line. These important effector-functions are also relevant in vivo as we found that higher frequencies of tumor-infiltrating NKp46pos Vd1 IELs in the colon-cancer specimens from patients undergone surgical gut resection significantly correlates with lower tumor progression and better prognosis. Taken together, our characterization of human gut-specific NKp46pos Vd1 T gd IEL pave the ground to better understand intestinal immune-homeostasis and immune-surveillance against colon-cancer tumor in order possibly develop novel clinical/prognostic markers and to dissect still unknown important pathogenic aspects of this disease.