The human melanoma cell line M24met metastasizes spontaneously from s.c. tumors to multiple distant sites in mice with severe combined immunodeficiency. Metastasis to lymph nodes and lungs is found in 100% of the animals. M24met has an undifferentiated phenotype and extra copies of the short arm of chromosome 7. This cell line expresses the epidermal growth factor receptor, and 425.3, a monoclonal antibody to the epidermal growth factor receptor, binds to 291,000 receptor molecules per M24met cell with a Kd of 2.3 × 10-19 m. This antibody has no effect on the proliferation of M24met cells under tissue culture conditions and does not mediate effector cell or complement-dependent cytotoxicity of these cells in vitro. However, treatment of established s.c. M24met tumors in mice with severe combined immunodeficiency with monoclonal antibody 425.3 specifically suppresses spontaneous metastasis of these tumors. Total doses of 4, 2, and 1 mg antibody per mouse decrease the number and size of melanoma metastases and prolong the life span of treated animals. Treatment with 4 mg of the F(ab′)2 fragment of monoclonal antibody 425.3 does not influence M24met melanoma metastasis, implying a significant contribution of the Fc portion to the antimetastatic effect of this antibody.