Toll-like receptor (TLR) 2 on antigen-presenting cells (APCs) enables these cells to recognize peptidoglycan-embedded lipopeptides and glycopolymers in the Staphylococcus aureus cell wall and mount an inflammatory response to this microbe. TLR2 signalling can also modulate immunity to S. aureus by inducing an interleukin (IL)-10 response in APCs. What determines the balance between proinflammatory and modulatory responses to S. aureus is unknown. We show that the modulatory IL-10 response preferentially occurs upon CD14- and CD36-independent TLR2 signaling, triggering PI3K activation, and is restricted to monocytes and monocyte-derived macrophages (MΦs). In contrast, monocyte-derived dendritic cells (DCs) produce mostly IL-12 and IL-23. The differential APC polarization induced by staphylococcal peptidoglycan translates into differential T helper responses: MΦs primarily trigger IL-10 and weak IL-17 responses, whereas DCs trigger a robust Th1/Th17 response. Exploitation of TLR2 signalling plasticity by S. aureus may explain the wide range of outcomes of human encounters with this microbe.