Ascaris suum is a helminth parasite of pigs closely related to its human counterpart, A. lumbricoides, which infects almost one billion people. Ascaris spp. is thought to modulate host immune and inflammatory responses, which may drive immune hyporesponsiveness during chronic infections. Using transcriptomic analysis, we show here that pigs with a chronic A. suum infection have a substantial suppression of inflammatory pathways in the intestinal mucosa, with a broad down-regulation of genes encoding cytokines and antigen-processing and co-stimulatory molecules. A. suum body fluid (ABF) supressed similar transcriptional pathways in human dendritic cells (DCs) in vitro. DCs exposed to ABF secreted minimal amounts of cytokines and had impaired production of cyclooxygengase-2, altered glucose metabolism, and a reduced capacity to induce IFN-γ production in T-cells. Our in vivo and in vitro data provide an insight into mucosal immune-modulation during Ascaris infection, and show that A. suum profoundly suppresses immune and inflammatory pathways.