Killer-cell immunoglobulin-like receptors (KIRs) regulate the killing function of NK cells, which play an important role in the antibody-dependent cell-mediated cytotoxicity (ADCC) response exerted by therapeutic monoclonal antibodies (mAbs). However, it is unknown whether the extensive genetic variability of KIR genes and/or their HLA ligands might influence the response to these treatments. This study aimed to explore whether the variability in KIR/HLA genes may be associated to the variable response observed to mAbs-based anti-EGFR therapies. Thirty-nine patients treated with anti-EGFR mAbs (trastuzumab for advanced breast cancer, or cetuximab for advanced colorectal or advanced head and neck cancer), were included in the study. All the patients had progressed to mAbs therapy and were grouped into two categories taking into account time to treatment failure (TTF ≤6 months and TTF ≥10 months). KIR genotyping (16 genetic variability) was performed in genomic DNA from peripheral blood by PCR sequence-specific primer technique and HLA ligand typing was performed for HLA-B & -C loci by reverse PCR-SSO methodology. Subjects carrying the KIR/HLA ligand combinations KIR2DS1/HLAC2C2-C1C2 and KIR3DS1/HLABw4w4-w4w6 showed longer TTF than non-carriers counterparts (14,76 m vs 3,73 m, p<0.001, and 14,93 m vs 4,6 m, p=0.005 respectively). No other significant differences were observed. Two activating KIR/HLA ligand combinations predict better response of patients to anti-EGFR therapy. These findings increase the overall knowledge on the role of specific gene variants related with responsivenessto anti-EGFR treatment in solid tumours and highlight the importance of assessing gene polymorphisms related with cancer medications.