By catalyzing generation of hydrogen peroxide (H202) in enterocytes, DUOX2 participates in innate defense against intestinal microbes.1,2 One monoallelic exonic variant of DUOX2 was recently found in 15 out of 19 Crohn disease-affected patients in a large Ashkenazi family.3 Herein, we report the first identification of biallelic, inherited mutations of DUOX2 as a Mendelian cause of very early onset inflammatory bowel disease (VEO-IBD) in a boy born from unrelated parents of Italian origin. The patient developed pancolitis with bloody diarrhea at the age of 3.