Fine-tuning of cytokine-inducing pathways is essential for immune homeostasis. Consistently, a dysregulated increase or decrease in pattern-recognition receptor (PRR)-induced signaling and cytokine secretion can lead to inflammatory bowel disease. Multiple gene loci are associated with inflammatory bowel disease, but their functional effects are largely unknown. One such region in chromosome 2q12 (rs917997), also associated with other immune-mediated diseases, encompasses IL18RAP. We found that human monocyte-derived macrophages (MDMs) from rs917997 AA risk carriers secrete significantly less cytokines than G carriers upon stimulation of multiple PRRs, including nucleotide-binding oligomerization domain 2 (NOD2). We identified that IL-18 signaling through IL-18RAP was critical in amplifying PRR-induced cytokine secretion in MDMs. IL-18RAP responded to NOD2-initiated early, caspase-1–dependent autocrine IL-18, which dramatically enhanced MAPK, NF-κB, PI3K, and calcium signaling. Reconstituting MAPK activation was sufficient to rescue decreased cytokines in NOD2-stimulated IL-18RAP–deficient MDMs. Relative to GG carriers, MDM from rs917997 AA carriers had decreased expression of cell-surface IL-18RAP protein, as well as of IL-18R1 and IL-1R1, genes also located in the IL18RAP region. Accordingly, these risk-carrier MDMs show diminished PRR-, IL-18–, and IL-1–induced MAPK and NF-κB signaling. Taken together, our results demonstrate clear functional consequences of the rs917997 risk polymorphism; this polymorphism leads to a loss-of-function through decreased IL-18RAP, IL-18R1, and IL-1R1 protein expression, which impairs autocrine IL-18 and IL-1 signaling, thereby leading to decreased cytokine secretion in MDMs upon stimulation of a broad range of PRRs.