Active cellular motility and invasion play essential roles in metastasis. Introduction of normal, neo-tagged human chromosome 6 (neo6) into highly metastatic human melanoma cell line C8161 results in complete suppression of metastasis in vivo. To understand the mechanism by which metastasis was inhibited in neo6/C8161 hybrids, two in vitro assays, pseudopod protrusion and Membrane Invasion Culture System, were used to measure motility and invasion, respectively. neo6/C8161 hybrids are much less motile although they remained invasive, indicating that a metastasis-suppressor gene(s) on human chromosome 6 may regulate cellular motility, thereby inhibiting metastasis. © 1995 by Academic Press, Inc.