Abstract: Induction of humoral anti-human high molecular weight melanoma-associated antigen (anti-HMW-MAA) immunity following active specific immunotherapy is associated with a statistically significant prolongation of survival in patients with melanoma. This association does not appear to be mediated by immunological mechanisms because anti-HMW-MAA antibodies are poor mediators of complement- and cell-mediated cytotoxicity of melanoma cells. Therefore, we have been investigating nonimmunological mechanisms by which anti-HMW-MAA antibodies (Abs) affect the biology of melanoma cells. We have demonstrated that anti-HMW-MAA mAbs interfere with the interaction of HMW-MAA with extracellular matrix (ECM) components, a process known to be crucial in the early phase of melanoma metastasis. Furthermore, anti-HMW-MAA mAbs appear to block the series of signal transduction events triggered by the interaction of HMW-MAA with ECM. They include the activation of the family of Rho GTPases, p130cas, and focal adhesion kinase (FAK). These findings parallel the inhibition of the rat homologue of HMW-MAA NG2 function by anti-NG2 antibodies. Taken together, all these results provide a mechanistic explanation not only for the therapeutic effect of anti-HMW-MAA antibodies in the treatment of melanoma, but also for the function of HMW-MAA in the biology of melanoma cells. This information is expected to serve as a useful background to design effective HMW-MAA-targeted immunotherapy in patients with melanoma.