Recent findings indicate that variable expression of beta 1 integrins may play a role in differential melanoma cell motility. Primary melanoma (PM) and metastatic melanoma (MM) cultures, derived from the same patient, were tested for their beta 1, alpha 2, alpha 3 and alpha 6 integrin subunit expression and cell migration on type IV collagen (CN IV) or laminin (LN). The MM cell line expressed markedly increased levels of the beta 1, alpha 2 and alpha 3, but not alpha 6 subunit compared to the PM cell line. The MM cell migration rate was significantly higher than that of the PM cell line on LN- or CN IV-coated substrates. Furthermore, the cell migration rate of both lines was significantly higher (p < 0.001) on these substrates than on the control substrates. The MM and PM cell migration was significantly inhibited by function-blocking anti-beta 1 and anti-alpha 3 MAbs, but not by the anti-alpha 6 MAb tested. In contrast, the anti-alpha 2 MAb significantly inhibited MM but not PM cell migration. These data show that the alpha 3 subunit plays a significant role in melanoma cell motility on CN IV and LN and that the alpha 2 subunit has a significant contribution to the motility of the MM cell line.