Psoriasis is a common autoimmune disease of the skin, characterized by hyperproliferation of epidermal cells. The role of the innate immune system in driving this autoimmune process has been proposed but remains unclear. This study demonstrates that plasmacytoid predendritic cells (PDCs), which are natural producers of interferon (IFN)-α, infiltrate the skin of psoriatic patients and become activated early in the disease process. In a xenograft model of human psoriasis, blocking IFN-α signaling or inhibiting PDCs from producing IFN-α prevented the T cell-dependent development of psoriasis. Furthermore, experiments showed that PDC-derived IFN-α is essential for driving the development of psoriasis in vivo. These findings identify a novel innate immune pathway that initiates psoriasis and suggest that PDCs and IFN-α may represent potential early targets for the treatment of this disease.Psoriasis is a common autoimmune disease of the skin, characterized by hyperproliferation of epidermal cells. The role of the innate immune system in driving this autoimmune process has been proposed but remains unclear. This study demonstrates that plasmacytoid predendritic cells (PDCs), which are natural producers of interferon (IFN)-α, infiltrate the skin of psoriatic patients and become activated early in the disease process. In a xenograft model of human psoriasis, blocking IFN-α signaling or inhibiting PDCs from producing IFN-α prevented the T cell-dependent development of psoriasis. Furthermore, experiments showed that PDC-derived IFN-α is essential for driving the development of psoriasis in vivo. These findings identify a novel innate immune pathway that initiates psoriasis and suggest that PDCs and IFN-α may represent potential early targets for the treatment of this disease.