IL-1β is a potent pro-inflammatory cytokine and a therapeutic target in several chronic inflammatory and autoimmune states. Monocytes and macrophages are the major sources of IL-1β. IL-1β production by these cells requires toll-like receptor (TLR) and adenosine triphosphate (ATP)-mediated P2X purinoceptor 7 (P2X7) signals, which together activate the inflammasome. However, how TLR signals and ATP availability are regulated during monocyte activation is unclear and the involvement of another danger signal system has long been proposed. Here, we demonstrate that both lipopolysaccharide (LPS) and the anaphylatoxin C3a, a complement cleavage fragment, are needed for IL-1β production in human macrophages and DCs, while in monocytes, C3a enhanced the secretion of LPS-induced IL-1β. C3a and LPS-stimulated monocytes increased Th17 cell induction in vitro, and human rejecting but not non-rejecting kidney transplant biopsies were characterized by local generation of C3a as well as monocyte and Th17 cell infiltration. Mechanistically, C3a drives IL-1β production in monocytes by controlling the release of intracellular ATP into the extracellular space via regulation of, yet unidentified, ATP-releasing channels in an ERK1/2-dependent fashion. These data define a novel function for complement in inflammasome activation in monocytes and suggest that C3aR-mediated signaling is a vital component of the IL-1β-Th17 axis.