Glucocorticoids such as dexamethasone are widely used as comedication in the treatment of head and neck cancer, e.g., to improve appetite and decrease weight loss and fatigue in patients with advanced disease or as antiallergic and antiemetic prophylaxis during anti-EGFR therapy. However, the literature suggests that dexamethasone induces resistance to antineoplastic agents in many solid tumor models in vitro and in vivo. Since this phenomenon has never been investigated in head and neck cancer, the present study was conducted to investigate the effect of dexamethasone on the antiproliferative activity of cetuximab in vitro in squamous cell carcinoma of the head and neck (SCCHN) cell lines. The antiproliferative effect of the anti-EGFR agent cetuximab alone and in combination with increasing concentrations of dexamethasone was examined in eight SCCHN cell lines at three different time-points (24, 48 and 72 h). Cell growth inhibition and viability were measured quantitatively using WST and LDH assays. Absolute tumor cell numbers were determined by cell counting in a Rosenthal chamber. Cetuximab alone inhibited the growth of all eight SCCHN cell lines significantly (p=0.008). In some cases the addition of dexamethasone reduced the antiproliferative activity of cetuximab (p<or=0.038) but remained significant in all of the eight SCCHN cell lines compared with untreated controls (p<or=0.028) at each drug concentration and each time-point. In contrast to the results reported for other tumor models, in our study dexamethasone showed in the majority of the evaluated dexamethasone drug concentrations and time-points no inhibition of the cytotoxic activity of cetuximab. The reasons for these discrepant findings are unclear but may be related to the degree of tumor cell differentiation or proliferation rate. Thus, further studies are required to elucidate the molecular mechanisms underlying the interaction between dexamethasone and cetuximab in different tumors.