Collagen XVII is a hemidesmosomal anchorage molecule of basal keratinocytes that promotes stable epidermal-dermal adhesion. One unique feature of collagen XVII is that its collagenous ectodomain is constitutively released from the cell surface by disintegrin and metalloproteinases (ADAMs) through cleavage within its juxtamembraneous linker domain. The responsivity of shedding to environmental stimuli and the high stability of the released ectodomain in several tissues suggests functions in cell detachment during epidermal morphogenesis, differentiation and regeneration, but its physiological relevance remained elusive. To investigate this, we generated knock-in mice, which express a functional non-sheddable collagen XVII mutant with a 41 amino acid deletion in the linker domain spanning all ADAM cleavage sites. These mice showed no macroscopic phenotypic changes, were fertile and had a normal life span. Prevention of collagen XVII shedding interfered neither with skin development nor with epidermal adhesion and differentiation. However, it led to faster wound closure due to accelerated re-epithelialization at the wound edges where shedding of wild type collagen XVII was strongly induced. Taken together, we have successfully generated a functional non-shedding collagen XVII mouse model, which represents a powerful tool to investigate the pathophysiological relevance of ectodomain shedding during wound regeneration and cancer invasion.