Animal tumor models are still essential for the development of new medication and therapy concepts. In the field of human oral squamous cell cancer, there are few reliable xenografted tumor models available. Therefore, during a two-course experiment, we established a new xenografted tumor model of human oral squamous cell cancer. The tumor growth rates of two different tumor cell lines were compared in the inbred immunodeficient CD-17-RAG 2 mouse, NMRI-SCID mouse (scid/scid), and Swiss nude mouse (nu/nu). The tumor cell line from a lymphnode metastasis of an oral squamous cell carcinoma (XF 354) had a faster growth rate and a more characteristic histology than did the cell line from the primary tumor of a squamous cell carcinoma of the floor of the mouth (UM-SCC-14C). The highest tumor growth rate was observed in the RAG 2 mouse, followed by the SCID mouse. The Swiss nude mouse showed no tumor growth. The combination of the XF 354 tumor cell line and the RAG 2 mouse was most successful, with a tumor growth rate of 95%. Our animal model is very reliable and allows manipulations for as long as 30 min under anesthesia outside of microbiologic safety cabinets, where the handling of animals is much more comfortable and less time-consuming. The tumor histology was easily interpreted by using light microscopy. Steps for cell cultivation and tumor implantation are described and discussed. Therefore we strongly recommend the use of the model comprising the RAG 2 mouse with the xenografted cell line XF 354 for research in the field of human oral squamous cell carcinoma.