The mechanism by which mutations in CARD15, which encodes nucleotide-binding oligomerization domain 2 (NOD2), cause Crohn disease is poorly understood. Because signaling via mutated NOD2 proteins leads to defective activation of the transcription factor NF-κB, one proposal is that mutations cause deficient NF-κB-dependent T helper type 1 (T_H1) responses and increased susceptibility to infection. However, this idea is inconsistent with the increased T_H1 responses characteristic of Crohn disease. Here we used Card15^−/− mice to show that intact NOD2 signaling inhibited Toll-like receptor 2–driven activation of NF-κB, particularly of the NF-κB subunit c-Rel. Moreover, NOD2 deficiency or the presence of a Crohn disease–like Card15 mutation increased Toll-like receptor 2–mediated activation of NF-κB–c-Rel, and T_H1 responses were enhanced. Thus, CARD15 mutations may lead to disease by causing excessive T_H1 responses.