Near-infrared photoimmunotherapy (NIR-PIT) represents a novel antibody-based strategy for selective cellular depletion. Originally introduced for EGFR-specific cancer cell treatment, NIR-PIT displayed distinctive depletion prosperity in several mouse models. Adapted from these findings, a skin selective depletion of an antibody-targeted cell type has a potential of becoming an important therapeutic option in dermatology. Here, we report on a method for the skin selective depletion of CD8 T cells and its therapeutic effect in a humanized mouse model of cutaneous acute graft-versus-host disease (aGVHD). In immunodeficient NSG (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) mice transplanted with human skin, aGVHD was induced by intravenous injection of mismatched peripheral blood mononuclear cells which resulted in a strong T cell infiltration, inflammation and epithelial skin graft rejection. Skin specific ablation of target cells was induced by the combined function of immuno- and phototherapy activated by near-infrared light. Our data demonstrates strong ablation success by selectively killing skin localized CD8 T cells while sparing systemic immunosuppression. The effect proved to be highly efficient by inhibiting the manifestation of cutaneous aGVHD and diminished the expression of pathological and skin specific biomarkers. Therefore, we hypothesize that localized depletion using NIR-PIT inhibits cutaneous aGVHD mediated by cytotoxic CD8 T cells but prevents systemic ablation, which would reduce marrow engraftment and tumor clearance. Moreover, this study describes the first skin-selective therapeutic success of applying NIR-PIT in a model of human inflammatory skin disease and demonstrates that NIR-PIT can serve as a therapeutic approach for clinical use in dermatology.