Recently, the suppressor of cytokine signaling (SOCS)-3 has been shown to be expressed in disturbed wound margin epithelia during diabetes-impaired wound healing in mice. To functionally connect a potential contribution of SOCS-3 expression to the control of wound keratinocyte behavior in skin repair, we created a transgenic mouse (tsgn-K5/SOCS3) overexpressing SOCS-3 in keratinocytes using the bovine keratin 5 promoter. Tsgn-K5/SOCS3 mice showed a constitutive expression of SOCS-3 in the basal layer of skin epidermis. Keratinocytes of tsgn-K5/SOCS3 mice showed full inhibition of signal transducer and activator of transcription (STAT)-3 phosphorylation. Tsgn-K5/SOCS3 keratinocytes also showed a strong inhibition of migratory and proliferative potential in vitro. In addition, tsgn-K5/SOCS3 keratinocytes co-expressed the differentiation marker loricrin in the basal layer of nonwounded skin in vivo. Upon wounding, wound tissues of tsgn-K5/SOCS3 mice showed an impairment of wound closure characterized by strongly atrophied wound margin epithelia. Atrophied epithelia of tsgn-K5/SOCS3 mice exhibited a marked reduction in proliferating cells and reduced total keratinocyte numbers. In summary, this study suggests that the presence of SOCS-3 in keratinocytes strongly disturbs epithelial repair of cutaneous wounds by interfering with keratinocyte proliferation and migration.