Although in vivo behavior of many human tumor cell lines can be studied in animal models such as nude mice, several such cell lines cannot be grown in immunodepressed hosts, even when inoculated at high cell doses. In an attempt to reproduce the diffuse invasive growth of human oral squamous cell carcinoma (HOSCC) in nude mice, we managed to stimulate the tumor growth of nontumorigenic HOSCC cell lines by means of the co-inoculation of these cells and Matrigel into nude mice. HOC313 and TSU cell lines, established from HOSCC with the diffuse invasive type diagnosed as grade "4D" by means of the Yamamoto and Kohama classification, were used. A total of 4 X 10(6) cells was co-injected with Matrigel into the tongue or the oral floor of nude mice. The mice were sacrificed when the size of the subcutaneous tumors reached 6-8 mm in diameter, and then subjected to autopsy and histological examination. The two cell lines formed tumors in the tongue or the oral floor of nude mice. Histologically, these tumors showed diffuse invasion into the surrounding tissues and their histological appearance was similar to that of the original tumors.