A human squamous cell carcinoma (SCC) from the floor of the mouth (FOM) was implanted by a needle aspiration technique in the FOM site of athymic nude mice. Mice were killed at 3-week intervals, and the oral cavity, mandible, and neck were sectioned and examined histologically. Tumor growth was observed in 65% of the animals, with histologic features consistent with the engrafted human invasive SCC. These features included invasion of connective tissue in 92%, invasion of muscle in 77%, invasion and destruction of bone in 54%, and vascular invasion in 15% of the mice. In contrast, FOM tumor implanted subcutaneously on back sites of nude mice was totally encapsulated by fibrous connective tissue with evidence of capsular invasion. SCC from other head and neck sites showed similar locally invasive growth after intraoral implantation in nude mice. The results demonstrate the invasive characteristics of human head and neck SCC grown in the homologous oral cavity site in nude mice and support the nude mouse as a biologically relevant in vivo model in the investigation of the biologic characteristics and therapy of head and neck carcinoma.