While monocyte chemotactic protein-1 (MCP-1) is best known for its ability to recruit mononuclear cells, few studies have examined the effects of this chemokine on other events in the vascular response to injury. The purpose of the present study was to determine the influence of MCP-1 on human vascular smooth muscle (VSMC) proliferation. MCP-1 induced concentration-dependent VSMC proliferation as measured by BrdU uptake. Direct cell counting demonstrated a 2-fold increase in VSMC following stimulation with MCP-1. This mitogenic effect was similar to that observed with the prototypical atherogenic cytokine, platelet derived growth factor. Immunohistochemistry and western blot analysis revealed that MCP-1 increased both proliferating nuclear cell antigen and cyclin A expression. While MCP-1 did not promote nuclear factor kappa B activation, MCP-1-induced VSMC proliferation appeared to be dependent upon phosphotidylinositol 3-kinase activation. In conclusion, MCP-1 directly induces VSMC growth which is associated with activation of cell cycle proteins and intracellular proliferative signals. Within the inflammatory paradigm of vascular remodeling, these data suggest that MCP-1 is more than simply a chemokine, but also a potent mitogen for VSMC proliferation.