The antigen-specific T-cell unresponsiveness seen in lymphatic filariasis is mediated, in part, by diminished antigen-presenting cell function and is most specific for microfilariae (MF), the parasite stage found in large numbers in the peripheral circulation. We investigated the effect of MF antigen (MFAg) on dendritic cells (DC) in both their differentiation process from monocyte precursors and also after they have developed into DC. When MFAg was added to cultures of monocytes during their differentiation process to immature DC, the production of interleukin 12 (IL-12) p40, p70 protein, and IL-10 was significantly (P < 0.03) inhibited in response to Staphylococcus aureus Cowan (SAC) and SAC-gamma interferon (IFN-γ) (60% to 80% inhibition). IL-10 was also inhibited (P = 0.04) in response to CD40 ligand–IFN-γ. Moreover, MFAg inhibited the mRNA expression of IL-12 p40 and IL-10 as assessed by RNA protection assays. This effect was antigen specific, as another parasite antigen (soluble Toxoplasma gondii antigen) did not inhibit the production of these cytokines. This effect was also not a result of diminished cell viability nor of an alteration in surface expression of most costimulatory surface molecules, including major histocompatibility complex class I and class II. In contrast to exposure throughout the differentiation process, MFAg added to immature DC had no effect on DC cytokine expression. Although MF-differentiated DC were capable of inducing an allogeneic mixed lymphocyte reaction, they did so to a significantly lesser degree than DC without antigen exposure. These data collectively suggest that once DC are differentiated from their precursor cells, they become resistant to changes by MFAg.