In this study, we examined the effect of tumor necrosis factor α (TNF-α) on pulmonary metastasis of murine melanoma B16-BL6 by focusing on the intercellular adhesion molecules involved in the metastatic process. TNF-α administration before B16-BL6 inoculation significantly enhanced the experimental pulmonary metastasis. The enhancement was seen when TNF-α was administered 4 h, but not 24 h, before B16-BL6 inoculation. Administration of 50–5000 units of TNF-α increased the number of metastatic lung colonies in a dose-dependent manner. Flow cytometric analysis demonstrated a high expression of very late activation antigen 4 (VLA-4) on the surface of B16-BL6 cells. Immunoperoxidase staining demonstrated that a ligand for VLA-4, vascular cell adhesion molecule 1, was expressed on lung vascular endothelium 4 h after administration of TNF-α. Pretreatment of B16-BL6 cells with an anti-VLA-4 monoclonal antibody abolished the TNF-α-enhanced pulmonary lung colonies. Administration of an anti-vascular cell adhesion molecule 1 monoclonal antibody also abolished the enhancement. These results indicate that the interaction between VLA-4 on tumor cells and vascular cell adhesion molecule 1 on activated endothelial cells is critically involved in TNF-α enhancement of metastasis.