In comparison to the rat, the anatomy of the mouse hippocampus, and in particular the response to entorhinal cortex lesioning, is less well characterised. Here we studied the axonal sprouting response after lesioning of the entorhinodentate perforant path projection in young adult SJL/J and C57BL/6 mice. We found that lesioning led to translaminar sprouting of Timm stained regio inferior hippocampus (CA3)-associated fibre systems into the denervated termination zones of the CA3 and dentate gyrus, from the adjacent non-denervated stratum radiatum of CA3. Differences were seen in the Timm staining pattern of the two strains of mice, while the response to lesioning appeared similar albeit less pronounced than that observed in the rat. We also observed an intensified acetylcholine esterase staining reflective of cholinergic sprouting in the denervated perforant path termination zones, which was particularly prominent in areas with sprouting of Timm stained CA3-associated fibres. Finally, we showed that some of the sprouting fibres within the CA3 were myelinated, due to an increased density of silver impregnated myelinated fibres in this region after lesioning. These results show that the basic characteristics of the response to perforant path lesioning in mice are similar to those in the rat, but suggest that the magnitude of the response in the two species is different.