Microglia and astroglia have been thought to govern the survival of neurons after damage to the CNS. To investigate these putative glia- neuron relationships, we examined microglia and astroglia secretion products for effects upon growth of cultured neurons. Activated microglia secrete small neurotoxic factors (< 500 Da), while astroglia constitutively release proteins (> 10 kDa) that promote neuronal growth. Proteins released from astroglia, moreover, attenuate microglial toxicity, suggesting that different glial populations have opposing actions upon neuronal survival. Further study shows that neurotoxins from microglia are heat-stable, protease-resistant molecules with biologic activities blocked by NMDA receptor antagonists. Microglial factors, although toxic for chick ciliary neurons and rat spinal cord neurons, did not reduce numbers of oligodendroglia, astroglia, or Schwann cells in culture. The microglial neurotoxins can be distinguished from cytokines, from free radical intermediates, from the excitatory amino acids glutamate or aspartate, and from the NMDA receptor-mediated toxin quinolinic acid. We propose that secretion products from reactive microglia, but not astroglia, endanger surviving neurons after CNS injury by release of a novel class of neuron-killing molecules.