Axons in both peripheral nerves and central fiber pathways undergo very slow Wallerian degeneration in Wlds mutant mice. It has recently been shown that in Wlds mutant mice there is a delay in the intensification of acetylcholinesterase histochemical staining in the molecular layer of the dentate gyrus following lesions of the entorhinal cortex. Thus, it appears that delayed post-lesion reactive sprouting is associated with the delayed degeneration of cut central axons in this mutant. We have studied the time course of changes in the septohippocampal and the hippocampal commissural projections following interruption of perforant path in Wlds mutant mice and in normal (C57BL/6J) mice using the anterograde tracer, wheat germ agglutinin conjugated horseradish peroxidase. In normal mice, changes in the distribution of labeled septal and commissural axons indicative of sprouting are seen in the dentate molecular layer as early as 3 days post-lesion. The earliest survival time at which similar changes are found in Wlds mutant mice is seven days post-lesion, when an increase in the density of labeled septal axons begins in the outer molecular layer. The delay in the sprouting of commissural axons in the mutant is even longer. Changes in the distribution of labeled commissural axons in the dentate gyrus of Wlds mutant mice are first seen 12 days post-lesion. These results confirm that post-lesion reactive axonal sprouting can be delayed in the central nervous system of Wlds mutant mice. In addition, our results indicate that the extent of this delay may differ among axonal fiber systems. These findings are consistent with the notion that various central axonal systems may respond differentially to sprouting cues and are reminiscent of differences found in the regenerating response exhibited by sensory and motor axons in the Wlds mutant after peripheral nerve cuts.