AbstractTwenty 36‐hour infusions of high‐dose methotrexate were given preoperatively to 10 patients with head and neck cancer. Plasma methotrexate levels of greater than 1 × 10−5M were maintained for 36 hours and declined with primary and secondary plasma half‐lives of 1.7 and 9.2 hours following the end of the infusion. Toxicity of this infusion regimen was minimal (10% incidence of significant (WBC<2000/mm3) myelosuppression; no renal toxicity) and all patients underwent surgical resection within 3 weeks of therapy without obvious increase in operative complications. Four of ten patients responded to chemotherapy. Further comparison of the therapeutic efficacy of this prolonged preoperative infusion regimen with surgery alone or schedules employing conventional doses or 6‐hour infusions of high‐dose methotrexate appea