Versican is a large chondroitin sulfate proteoglycan belonging to the lectican family. Alternative splicing of versicangenerates at least four isoforms named V0, V1, V2, and V3. We have shown that the versican V1 isoform not only enhancedcell proliferation, but also modulated cell cycle progression and protected the cells from apoptosis. Futhermore, the V1isoform was able to not only activate proto-oncogene EGFR expression and modulate its downstream signaling pathway,but also induce p27 degradation and enhance CDK2 kinase activity. As well, the V1 isoform down-regulated theexpression of the proapoptotic protein Bad. By contrast, the V2 isoform exhibited opposite biological activities byinhibiting cell proliferation and down-regulated the expression of EGFR and cyclin A. Furthermore, V2 did not contributeapoptotic resistance to the cells. In light of these results, we are reporting opposite functions for the two versican isoformswhose expression is differentially regulated. Our studies suggest that the roles of these two isoforms are associated withthe subdomains CS and CS, respectively. These results were confirmed by silencing the expression of versican V1 withsmall interfering RNA (siRNA), which abolished V1-enhanced cell proliferation and V1-induced reduction of apoptosis.