The complement anaphylatoxin, C5a has been implicated in regulation of adaptive immune responses through modulation of APC function as shown mainly in studies in mice. C5a was shown to enhance cytokine production in immature DCs, but the effect of C5a on DC function during DC activation has not been elucidated in human. In this study we investigated the effect of C5a on human monocyte derived DCs when simultaneously stimulated with TLR ligands. While C5a indeed enhanced cytokine production of immature DCs, the addition of C5a inhibited production of IL-12, IL-23 and TNFα induced by various TLR ligands such as LPS, R848 and Pam(3)CSK(4). The inhibitory effect of C5a on LPS induced IL-6 production was less pronounced and LPS induced IL-10 was not affected at all. This indicates that C5aR signaling has a differential effect on human DC differentiation depending on the crosstalk with other receptors. Furthermore we found that C5a affects the LPS induced cytokines in a small time frame, and requires almost concurrent signaling of C5a receptor and TLR4. These data emphasize the complexity of DC regulation by anaphylatoxins. While complement activation may provide proinflammatory signals to immature DCs in the absence of pathogens, the same products may serve to downmodulate or deviate immune responses upon combat against infections. These context depending effects of anaphylatoxins on immune responses may have important implications for the emerging use of complement inhibitors in clinical practice.