We have examined the microglial reaction accompanying motor neuron death following sciatic nerve crush in the newborn rat using lectin staining with the Griffonia simplicifolia B4-isolectin, as well as immunocytochemistry with a panel of monoclonal antibodies directed against brain macrophage antigen (ED2), and various immunologically important surface molecules (immunomolecules), such as major histocompatibility complex (MHC) class II (Ia) antigen (OX-6), CR3 complement receptor (OX-42), CD4 antigen (W3/25), and leukocyte common antigen (OX-1). The lectin histochemical method provided the earliest indication of a microglial response by demonstrating increased microglial density and clustering around dying motoneurons as early as 2 days after lesioning. Most immunomolecules were largely undetectable in the normal and early post-lesion spinal cord; however, at post-lesion day 5 localized expression of Ia antigen was visualized in the area of degenerating motor neurons. Ia expression preceded the appearance of other immunomolecules at day 8. No increase in staining with the ED2 antibody for macrophage antigen could be detected at any post-lesion interval. When compared to the microglial activation that occurs after axotomy in adult animals, our results show a similar onset in microglial activation in neonatal animals; however, the duration of immunomolecule expression is much briefer.