We demonstrate a role for nonactivated rat microglia in the survival and maturation of oligodendrocyte precursor cells (OPCs). Media conditioned by nonactivated microglia increase the number of surviving galactocerebroside+ (GalC+) oligodendrocytes in vitro at 48 h by inhibiting the apoptosis of OPCs and stimulating their maturation to GalC+ oligodendrocytes. These effects are not observed with medium conditioned by microglia activated with interferon-γ (IFN-γ). Conditioned medium from nonactivated microglia is associated with upregulation in OPCs of nuclear factor of kappa binding (NF-κB) p65 subunit. The use of antisense to the inhibitor of kappa binding (IκB) induces p65 subunit activation in OPCs and, in common with medium conditioned by nonactivated microglia, also inhibits OPC apoptosis and promotes cell maturation. Anti-platelet-derived growth factor (PDGF) antibody abolishes this effect even though PDGF-A chain is expressed at similar levels within both nonactivated and IFN-γ-activated microglia and both conditioned media have similar levels of PDGF-A chain bioactivity. However, only conditioned medium from nonactivated microglia recruit phosphatidyl-3-inositol (PI-3) kinase to the PDGF-α receptor and synergise with endogenous PDGF-A chain to increase NF-κB activation. These results suggest that, dependent on their state of activation, microglia produce soluble factors that promote oligodendrocyte development through an effect on the PDGF-α receptor-signalling pathway.