IL-6 has been found to be a potent inhibitor of melanoma A375-C6 cell adhesion, in addition to its known action in arresting cells at G1/G0 phase of the cell cycle IL-6 treated melanoma cells were found to round up and to lose the ability to adhere to fibronectin, laminin, collagen, and tenascin over 72 to 96 hours of IL-6 treatment, a time course similar to that seen for cell cycle inhibition. Cell cycle inhibition and loss of adhesion were found, however, to be independent effects of IL-6. Analysis of cell surface integrins indicated significant changes in the expression of several integrins including downregulation of a3 and av beta 5 and upregulation of a3. However, the changes in integrin expression did not correlate with loss of adhesion to relevant ligands. Three A375 melanoma clones varying in metastatic potential also demonstrated inhibition of both cell proliferation and matrix adhesion by IL-6.