Eighty patients with recurrent squamous cell cancer of the head and neck were randomized to cisplatin (80 mg/m2) every 3 weeks or cisplatin plus weekly methotrexate (250 mg/m2) with leucovorin. The overall response rate to cisplatin was 18%, with 10% complete responses. The overall response to the combination was 33% with 18% complete responses (P = 0.11). There was no difference in response duration, time to progression, or survival. There was no difference in renal toxicity between the 2 arms (creatinine greater than 2 mg/dl in 6% of the patients). There was significantly more leukopenia (64%), thrombocytopenia (18%), anemia (18%), and mucositis (33%) in the combination arm. This combination of two of the best agents for head and neck cancer did not improve response, but resulted in added toxicity.