CNTF (ciliary neurotrophic factor) has been suggested to be an important survival factor for oligodendrocytes; however, this effect is inconsistently obtained and myelination appears normal in CNTF null animals. On the other hand, CNTF stimulates astrocytes to produce growth and trophic factors. Therefore, we tested the hypothesis that CNTF acts indirectly through astrocytes to promote oligodendrocyte survival. We show that CNTF-stimulated astrocytes release a trophic factor(s) that leads to more than double the number of oligodendrocyte progenitor cells (OPCs) by 48 h. The trophic activity fractionates at greater than 30 kD. By contrast, OPCs grown in CNTF supplemented chemically defined medium fared no better than cells grown without CNTF. Untreated astrocytes, and CNTF- and IL-1beta -stimulated astrocytes all promoted the proliferation of OPCs to a similar extent, but only the CNTF-stimulated astrocyte conditioned media (CM) resulted in increased OPCs numbers. Cumulatively, these results confirm previous data indicating that astrocytes release potent mitogens for oligodendroglia, and demonstrate that CNTF stimulates astrocytes to release an OPC survival-promoting activity.