Abstract Pustular psoriasis is a devastating subtype of psoriasis associated with significant morbidity and mortality. Pustular psoriasis is the only form of psoriasis that shows prominent sex bias, with the majority of cases found in women. Pustular psoriasis, and to a lesser extent plaque psoriasis, is characterized by the prominent involvement of the IL-36 family of cytokines, which consists of three pro-inflammatory cytokines: IL-36A, IL-36B and IL-36G, and the IL-36 receptor antagonist (IL-36RA/IL36RN). All three IL-36 members and the IL-36 receptor antagonist are increased (5- to 10-fold) in psoriatic skin. Single-cell and spatial-seq data demonstrated that IL-36 responses are primarily localized to the supraspinous compartment of the epidermis and strongly correlate with and act downstream of both IL-17A and TNF responses. CRISPR/Cas9 targeted knocking out of each IL-36 family member in keratinocytes demonstrates that both IL36G and IL36R KOs, but not IL36A KO, suppress both IL-17A and TNF responses (P < 0.001). Notably, the suppressive role of IL36G KO occurred in the absence of neutrophil proteases, which have been considered primary activators of the IL-36 axis in the skin. Bulk RNA-seq data from primary keratinocytes (n = 47) showed marked sex bias in IL-36G response, with female keratinocytes having a more robust pro-inflammatory response to IL-36G compared with male keratinocytes (P < 0.001). Furthermore, female keratinocytes showed higher expression of the type I IFN, IFNK (P < 0.001; FC-3.84), and IFN signature genes, such as MX1 (P < 0.001; FC-4.78), indicating an association between IFN-κ and the IL-36 axis in female keratinocytes. These data provide novel insights into IL-36 biology, demonstrate its role in amplifying IL-17 and TNF responses in the epidermis, and suggest that the sex bias of IL-36 response may contribute to the marked female bias of pustular forms of psoriasis.