In the present study, we examined the antitumor effect of paclitaxel (PTX) in combination with cetuximab in oral squamous cell carcinoma (OSCC) and the mechanism of its enhanced antitumor activity. Treatment of OSCC (HSC2, HSC3 and HSC4) cells with PTX (0.02 µg/ml) and cetuximab (1 µg/ml) combination resulted in a significant inhibition of cell growth in vitro compared to either agent alone. Moreover, it was found by Hoechst 33258 staining that DNA fragmentation markedly occurred in OSCC cells treated with PTX and cetuximab combination treatment. Furthermore, PTX and cetuximab combination treatment reduced the expression of p65 (NF-κB) protein in OSCC cells. In our in vivo experiment, HSC2 tumor-bearing nude mice were treated with PTX (20 mg/kg/day, twice/week, 3 weeks) and/or cetuximab (20 mg/kg/day, twice/week, 3 weeks). Tumor growth was significantly suppressed by PTX and cetuximab combined treatment when compared to PTX or cetuximab alone, or the untreated control. TUNEL-positive cells were upregulated in HSC2 tumors treated with PTX and cetuximab. In addition, immunohistochemical staining revealed that expression of p65 was downregulated in HSC2 tumors treated with PTX and cetuximab. Our results indicate that cetuximab may enhance the effect of PTX in OSCC through the downregulation of PTX induced p65 expression. Therefore, the combination of PTX and cetuximab might be a promising option for OSCC treatment.