The effect of filarial infections on malaria-specific immune responses was investigated in Malian villages coendemic for filariasis (Fil) and malaria. Cytokines were measured from plasma and Ag-stimulated whole blood from individuals with Wuchereria bancrofti and/or Mansonella perstans infections (Fil+; n = 19) and those without evidence of filarial infection (Fil-; n = 19). Plasma levels of IL-10 (geometric mean [GM], 22.8 vs 10.4) were higher in Fil+ compared with Fil-, whereas levels of IFN-inducible protein (IP)-10 were lower in Fil+ (GM, 66.3 vs 110.0). Fil+ had higher levels of spontaneously secreted IL-10 (GM, 59.3 vs 6.8 pg/ml) and lower levels of IL-2 (1.0 vs 1.2 pg/ml) than did Fil-. Although there were no differences in levels of Staphylococcus aureus enterotoxin B-induced cytokines between the two groups, Fil+ mounted lower IL-12p70 (GM, 1.11 vs 3.83 pg/ml; p = 0.007), IFN-γ (GM, 5.44 vs 23.41 pg/ml; p = 0.009), and IP-10 (GM, 29.43 vs 281.7 pg/ml; p = 0.007) responses following malaria Ag (MalAg) stimulation compared with Fil -. In contrast, Fil+ individuals had a higher MalAg-specific IL-10 response (GM, 7318 pg/ml vs 3029 pg/ml; p = 0.006) compared with those without filarial infection. Neutralizing Ab to IL-10 (but not to TGFβ) reversed the down-regulated MalAg-specific IFN-γ and IP-10 (p < 0.001) responses in Fil+. Together, these data demonstrate that filarial infections modulate the Plasmodium falciparum-specific IL-12p70/IFN-γ secretion pathways known to play a key role in resistance to malaria and that they do so in an IL-10-dependent manner.