Cetuximab, an anti-epidermal growth factor receptor (EGFR) antibody, has been widely used fortherapy of several kinds of malignant diseases. However, the anticancer effect is incomplete. The purpose of this study was to examine the synergism between the herbal drug, Polysaccharide K, and Cetuximab against gastrointestinal cancer cell lines in vitro and in vivo.Two gastrointestinal cancer cell lines positive for EGFR expression were used for this study. In the in vivo study, mice were xenografted with cancer cell lines subcutaneously. Neither PSK nor Cetuximab suppressed cell proliferation. However, when both drugs were administered, cancer growth was suppressed significantly compared with treatment with Cetuximab alone. This study demonstrated that PSK has the potential to enhance Cetuximab’s effect on gastrointestinal cancer.