Fifty-two patients with persistent, recurrent and/or metastatic squamous cell cancer of the head and neck were treated with weekly edatrexate, 80 mg/m2. Nine patients had received previous adjuvant or neoadjuvant chemotherapy. Of the 46 eligible patients, two complete responses and one partial response were observed (6%, 95% confidence interval of 1-18%). The most common toxicities were myelosuppression and mucositis, but dermatologic toxicity was also observed in 25% of patients. Edatrexate appears to have limited activity in advanced head and neck cancer.