Congenitally athymic nude (nu/nu) mice have been used extensively as hosts to study the metastatic properties of xenografted human tumors. It has not been fully explored to what extent the metastatic behavior of human tumor xenografts reflects the intrinsic properties of the tumor cells and to what extent it is influenced artificially by the host. The purpose of the work reported here was to evaluate the potential usefullness of athymic mice for qualitative and quantitative assessment of the intrinsic metastatic properties of human tumor cells. Four human melanoma cell lines (A-07, D-12, R-18, U-25) were included in the study. Quantitative intradermal and intracranial transplantation assays were used to determine the tumorigenicity and immunogenicity of the cell lines. The metastatic behavior of the cell lines was studied by inoculating cells intra-arterially or intravenously (artificial metastases) or intradermally (spontaneous metastases). The influence of the host on the incidence of metastases was assessed by inoculating cells intravenously in immunologically modified athymic mice. Both the intradermal and intracranial tumorigenicity differed substantially between the cell lines. The host immune reactivity against heterotransplantation was significantly lower for D-I 2 than for A-07, R-I8 and U-25 cells. The incidence of metastases was influenced significantly by the host immune reactivity. The cell lines showed organ-specific metastatic patterns in athymic mice. The organs of preference were lungs for A-07 and D-12 cells, lymph nodes for R-I 8 cells, and brain for U-25 cells. The organ-specific metastatic pattern in athymic mice reflected the pattern of distant metastases in the donor patients. In addition, all cell lines gave rise to metastases in abdominal organ sites, but without organ specificity. The incidence of abdominal metastases was influenced significantly by the tumorigenicity of the cell lines. In conclusion, athymic mice appear to be excellent hosts for assessment of the organ specificity in the metastatic behavior of human tumors. The metastasis frequency of human tumors in athymic mice, however, might be a misleading quantitative measure of the intrinsic metastatic propensity of the tumor cells, owing to the cell-line-dependent host immune reactivity.