A preliminary study was undertaken to assess the sensitivity of sheep epidermal squamous cell carcinoma, in the head and neck region, to intra-arterial (IA) methotrexate (MTX) infusion. There was an objective tumor response (40-56% regression) in all three IA-infused sheep, whereas tumor progression was observed in all three animals treated intravenously (IV). Regional and systemic side effects were negligible in all cases. Technically, IA drug infusion in the sheep was an improvement on previous small animal models, with no problems related to arterial catheter insertion, blockage, or dislodgement, and tolerable infusion times being of markedly longer duration. The histological differentiation of moderately differentiated stage II lesions improved during therapy irrespective of clinical response, whilst the histology of well-differentiated stage III and IV tumors remained unchanged. Tumor cell cycle stage and ploidy characteristics, as determined by flow cytometric DNA analysis, were little affected by either mode of drug administration. It is concluded that sheep epidermal carcinoma is responsive to IA MTX, and that this animal model is the most appropriate yet utilised to study the comparative effects of IA and IV chemotherapy in the head and neck region.