Interleukin (IL)-26 is a signature T helper 17 cytokine described as aproinflammatory and antimicrobial mediator. So far, IL-26 has been reported in several immune-mediated inflammatory diseases, but its involvement in inflammatory skin disorders is poorly known. Here, we have investigated the role of IL-26 in hidradenitis suppurativa (HS), through its involvement in antimicrobial activity. IL-26 was assessed in patients with HS through gene expression and protein analysis at skin and circulating levels. Ex vivo HS organ skin cultures, together with IL-26 antibody treatment, were performed to determine the IL-26 activity. Peripheral blood mononuclear cells (PBMCs) from patients with HS and healthy controls were either silenced or not with IL-26 small interfering (si)RNA in order to measure its antimicrobial, cytotoxic and phagocytic activities against Staphylococcus aureus. Our results have shown that IL-26 is able to modulate the proinflammatory response at the immune cell level. IL-26 was increased in the plasma of patients with HS compared with healthy controls. Subsequently, we have explored the bactericidal, cytotoxic and phagocytic activities of PBMCs against S. aureus in patients with HS and healthy controls. These activities were lower in patients with HS than in controls. Remarkably, the killing activities were reduced when healthy control PBMCs were transfected with IL-26 siRNA. However, the transfection did not affect the killing activity of HS PBMCs, supporting the idea that IL-26 lacks efficacy in HS. In conclusion, our findings suggest that infection susceptibility in HS might be related to IL-26. Although the role of bacteria remains controversial in HS, this study supports that there is a defect of antimicrobial response in these patients.