Reactive changes in macrophages/microglia and astrocytes were evaluated following spinal cord injury in normal mice of the C57BL/6J strain and in mice carrying a mutation (WldS) which delays the onset of Wallerian degeneration in damaged axons. Crush injuries were produced at the T8 level by using an extradural approach; animals were allowed to survive for 2 days to 12 weeks, and spinal cords were prepared for immunocytochemistry using antibodies against Mac1 and glial fibrillary acidid protein (GFAP). In normal mice, Mac1-positive macrophages accumulated at the injury site by 4 days and immunostaining of these cells peaked at 6-8 days. Cells in the gray matter near the crush site and in the ascending dorsal column also exhibited increased Mac1 staining that was prominent at 1 week and remained high at 2-4 weeks. In mice carrying the WldS mutation, the accumulation of macrophages at the injury site and the increase in immunostaining of these cells were delayed, as were the increases in immunostaining in the gray matter and dorsal columns. Both normal and mutant mice exhibited pronounced increases in glial fibrillary acidic protein immunostaining at the edge of the crush site and for some distance both rostral and caudal to the injury; increased immunostaining was also prominent along the ascending dorsal columns. The center of the crush site, which contained connective tissue, remained completely unstained for GFAP. In normal mice, immunostaining for GFAP reached a peak at 1 week postinjury and then declined. In mice carrying the WldS mutation, increases in GFAP immunostaining did not reach a peak until 2-3 weeks postinjury. These results indicate that activation of macrophages, microglia, and astrocytes is delayed and prolonged in mice carrying the WldS mutation.