Mice are common models for the study of mammalian wound healing. However, the array of available phenotypes suggests that significant differences likely exist in the normal wound healing response between different mouse strains. It is therefore essential to understand the normal healing response for each mouse strain, anatomic site, and mechanism of injury when investigating the potential effects of therapeutic interventions upon the healing response. The objective of the present study was to characterize and compare the morphologic changes that occur in both the MRL/MpJ and C57bl/6 mice strains during the first 14 days following amputation at the midpoint of the second phalanx. Our results identify noticeable temporal and spatial differences between the two strains, particularly in the expression of CD34+ and CD133+ progenitor cells, the re-epithelialization of the wound and deposition of type I and type III collagen. Unlike other selected tissues in which MRL/MpJ mice demonstrate a capacity to completely regenerate lost tissue, the responses observed in this model of digit healing did not translate into a greater capacity to regenerate lost structures. Both mouse strains show a similar healing response by day 14.