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Staphylococcus aureus (Sa) is a major human pathogen that secrets a great variability of virulence factors, which are very effective at subverting the human immune system. Phenol-soluble modulin (PSM) peptide toxins are one group of these secreted virulence factors, which highly contribute to Sa pathogenicity and are not only able to modulate immune cells, but also to lyse blood cells. Dendritic cells (DCs) are professional antigen presenting cells that link the innate and the adaptive immune response. Previously, the analysis of mouse bone marrow-derived DCs showed that PSMs have the ability to impair their protective functions in the immune system. However, the impact of Sa PSM peptides on human DCs was hitherto unknown. We therefore analyzed in this study the effect of PSMα3 on human monocyte-derived DC (moDC) maturation and functions, like cytokine production, antigen uptake, and T cell stimulatory capacity upon simultaneous treatment with either LPS (Toll-like receptor (TLR)4 ligand) or Sa cell lysate (TLR2 ligand). PSMs were able to penetrate the moDC cell membrane and enter the cytosol upon transient pore formation without cell lysis as shown by imaging flow cytometry. Upon simultaneous treatment with TLR ligands PSMs impaired DC functions, like reducing antigen uptake via clathrin-mediated endocytosis, modulating DC maturation, and preventing cytokine production. As a consequence, the adaptive immune response was affected by impaired T helper (Th) 1 differentiation. Instead the frequency and proliferation of regulatory T cells (Treg) with suppressive capacity was increased. Moreover, this Treg induction was also observed in an allogenic and autologous autoimmune disease setting, when CD4+ T cells from patients with Th1/Th17-associated spondyloarthritis were co-cultured with PSMα3-treated mature DCs. Thus, PSMs from highly virulent Sa strains affect DC functions not only in the mouse, but also in the human system, by priming tolerogenic DCs (tDCs), which modulate the adaptive immune response and thereby probably increase the tolerance towards the bacteria. The ability of PSMα3 as a novel peptide to prime tDCs could be beneficial for clinical applications, like vaccination strategies. If this approach is feasible for treating autoimmune diseases in vivo, by either generating tDCs ex vivo or by the administration of PSMα3 has to be further investigated.