A prospective clinical trial was developed to evaluate efficacy, toxicity, and patient compliance to adjuvant chemotherapy following surgery and postoperative radiation therapy in patients with squamous-cell carcinoma of the head and neck with extracapsular spread of tumor in cervical metastases. Following postoperative radiation therapy, 18 courses of methotrexate (MTX) and 5-fluorouracil (5-FU) were administered over 6 months. Fifty patients were registered. A total of 771 doses were administered. Dose reduction was required 72 times. Therapy was stopped in one patient (2%) because of toxicity. Three patients (6%) refused to complete the adjuvant therapy. Adjusted 2-year no evidence of disease (NED) survival is 66%. This study demonstrates that patients with advanced squamous-cell carcinoma of the head and neck can undertake an aggressive program of adjuvant MTX/5-FU with acceptable compliance and toxicities. Preliminary data generated in this nonrandomized study support the call for a prospective randomized multiinstitutional trial of this program.