In an effort to improve the response rate of patients with advanced head and neck cancer, a clinical trial combining two infrequently studied drugs was conducted. Twelve patients with squamous cell carcinoma of the head and neck were treated with 3-day continuous infusions of etoposide (90 mg/m2/day) and doxorubicin (15 mg/m2/day). All patients had been heavily pre-treated with surgery, radiation therapy, and/or chemotherapy. No objective responses were observed in 9 evaluable patients. One patient maintained stable disease state for 4 months. The major toxicity was Grade 3 or 4 myelosuppression which occurred in 42% of administered cycles. Although single-agent etoposide and doxorubicin have shown response rates of 10%-40% in patients with squamous cell carcinoma of the head and neck, we were disappointed to find that the combination of etoposide and doxorubicin has little or no activity in patients with advanced head and neck cancer. The toxicity encountered with this combination was significant.