Intermediate filament proteins have been used to diagnose the origin of specific cells. Classically, vimentin is found in mesenchymal cells, and keratins are present in epithelial cells. However, recent evidence suggests that the coexpression of these phenotype-specific proteins augments tumor cell motility, and hence, metastasis. In the present study, we used the mouse L-cell model to determine if a direct correlation exists between the expression of additional keratins in these cells, which normally express only vimentin, and their migratory ability. Mouse L cells were transfected with human keratins 8, 18, and both 8 and 18. The results indicate that the cells expressing complete keratin filaments have a higher migratory and invasive ability (through extracellular matrix-coated filters) compared with the parental and control-transfected clones. Furthermore, there is an enrichment of keratin-positive cells from a heterogeneous population of L clones selected over serial migrations. This migratory activity was directly correlated with the spreading ability of the cells on Matrigel matrix, in which the keratin-positive transfectants maintain a round morphology for a longer duration, compared with the other L-cell populations. Collectively, these data suggest that keratins may play an important role(s) in migration, through a special interaction with the extracellular environment, thereby influencing cell shape.