Squamous cell carcinoma of the head and neck (SCCHN) is one of the most common malignancies worldwide, with low 5-year survival rates. Current strategies that block epidermal growth factor receptor (EGFR) have limited effects when administered as single agents. Targeting EGFR via intratumoral administration of phosphorothioate-modified antisense oligonucleotides has antitumor efficacy in xenograft models of SCCHN. Because intratumoral delivery of therapeutic agents has limited clinical application, the present study was undertaken to examine the therapeutic mechanisms of systemically delivered phosphorothioate-modified EGFR antisense oligonucleotides alone, or in combination with docetaxel, in a SCCHN xenograft model. EGFR antisense oligonucleotides were administered at 5 mg/kg i.p. daily in athymic mice bearing 1483 human SCCHN xenografts alone or in combination with docetaxel at 2.5 mg/kg i.p. once a week for 4 weeks. Administration of EGFR antisense oligonucleotides in combination with docetaxel improved antitumor efficacy and resulted in lower expression levels of EGFR, fewer proliferating cells, and more apoptotic cells in the tumors compared with controls. Systemic administration of phosphorothioated EGFR antisense oligonucleotides for 30 days increased the retention of docetaxel in the tumor by approximately 4-fold compared with tumors treated with docetaxel alone or docetaxel and EGFR sense oligonucleotides (P < 0.05). Combination of EGFR antisense oligonucleotides with low doses of docetaxel has antitumor efficacy, and it may be an effective treatment strategy for SCCHN.