OPN (osteopontin) is a secreted glycoprotein predominantly expressed in bone matrix and kidney tissue. More recently, a neuroprotective role has been attributed to this cytokine since it can be up-regulated by microglia in neurodegeneration and inflammation. We demonstrate the expression of OPN within primary cultured microglia. Microglia incubated in vitro with different concentrations (0.1 fM-1 nM) of recombinant OPN showed increased proliferation at 10 fM. Moreover, conditioned medium of LLC-PK1 cells, a pig renal epithelial cell line and a known source of secreted OPN, more than doubled the rate of proliferation of microglia. Addition of an anti-OPN polyclonal antibody completely reversed this effect. Treatment with OPN dose-dependently also inhibited microglial superoxide production. In contrast, phagocytosis of fluorescent-labelled beads was enhanced by OPN. In conclusion, OPN shifts microglia, at least in vitro, to an alternative functional profile more fit to the immune-balanced microenvironment of the CNS (central nervous system).