Cetuximab, an IgG1 monoclonal antibody against the epidermal growth factor receptor (EGFR), is widely used for the treatment of metastatic colorectal cancer (mCRC). One of the mechanisms of action is considered to be antibody-dependent cell-mediated cytotoxicity (ADCC) triggered by Fcγ-R on natural killer cells. However, whether ADCC is associated with EGFR expression and/or the mutational status of EGF downstream effectors (KRAS and BRAF) in colorectal cancer (CRC) remains unclear. The aim of the present study was to verify whether ADCC activities are associated with the cell surface expression levels of EGFR and/or the mutational status of KRAS and BRAF. Five human CRC cell lines with different cell surface expression levels of EGFR and different KRAS and BRAF mutational statuses were selected to evaluate ADCC activity using peripheral blood mononuclear cells (PBMCs) from healthy human donors. Furthermore, tumor cells from resected specimens of CRC patients were used to evaluate the cell surface expression level of EGFR using immunohistochemistry and the KRAS and BRAF mutational statuses using direct sequencing, while the ADCC activity was examined using PBMCs from the same CRC patients. A strong correlation was observed between the expression levels of EGFR and the ADCC activities in the cell lines (correlation coefficient: 0.949; P= 0.003). Of the 13 resected specimens, a high ADCC activity level was significantly observed in tumor cells with high expression levels of cell surface EGFR, when compared with that in the tumor cells with low expression levels (P= 0.027). In both CRC cell lines and tumor cells from CRC patients, the ADCC activities were significantly associated with the cell surface expression levels of EGFR [standard partial regression coefficients: 0.911 (P= 0.017) and 0.660 (P= 0.018), respectively], but not with the mutational status of KRAS and BRAF [standard partial regression coefficient:-0.101 (P= 0.631) and 0.160 (P= 0.510), respectively]. Cetuximab-mediated ADCC activity may be correlated with the cell surface expression level of EGFR, regardless of the mutational statuses of KRAS and BRAF, in CRC.