Ileocecal resection (ICR) is frequently performed in Crohn’s disease (CD).NOD2mutations are risk factors for CD.Nod2knockout (ko) mice show impaired anastomotic healing after extended ICR. We further investigated the role of NOD2 after limited ICR. C57B16/J (wt) andNod2ko littermates underwent limited ICR including 1–2 cm terminal ileum and were randomly assigned to vehicle or MDP treatment. Bursting pressure was measured on POD 5, and the anastomosis was analyzed for matrix turn-over and granulation tissue. Wound fibroblasts from subcutaneously implanted sponges were used for comparison. The M1/M2 macrophage plasma cytokines were analyzed. Mortality was not different between groups. Bursting pressure was significantly decreased in ko mice. This was associated with less granulation tissue but was not affected by MDP. However, anastomotic leak (AL) rate tended to be lower in MDP-treated ko mice (29% vs. 11%,p= 0.07). mRNA expression ofcollagen-1α (col1 α),collagen-3α (col3 α),matrix metalloproteinase(mmp)2andmmp9was increased in ko mice, indicating increased matrix turn-over, specifically in the anastomosis. Systemic TNF-α expression was significantly lower in ko mice. Ileocolonic healing is impaired inNod2ko mice after limited ICR by local mechanisms maybe including local dysbiosis.