To clarify the mechanism of limb regeneration that differs between mammals (non-regenerative) and amphibians (regenerative), responses to limb amputation and the accessory limb inducible surgery (accessory limb model, ALM) were compared between mice and Xenopus, focusing on the events leading to blastema formation. In both animals, cartilaginous calluses were formed around the cut edge of bones after limb amputation. They not only are morphologically similar but show other similarities, such as growth driven by undifferentiated cell proliferation and macrophage-dependent and nerve-independent induction. It appears that amputation callus formation is a common nerve-independent regenerative response in mice and Xenopus. In contrast, the ALM revealed that the wound epithelium (WE) in Xenopus was innervated by many regenerating axons when a severed nerve ending was placed underneath it, whereas only a few axons were found within the WE in mice. Since nerves are involved in induction of the regeneration-permissive WE in amphibians, whether or not nerves can interact with the WE might be one of the key processes separating successful nerve-dependent blastema formation in Xenopus and failure in mice.