Common variable immune deficiency (CVID) and chronic granulomatous disease (CGD) are two of the well-characterized primary immune deficiencies with distinct pathologic defects. While CVID is predominantly a disorder of the adaptive immune system, in CGD, innate immunity is impaired. In both syndromes, the clinical manifestations include an increased susceptibility to infections and a number of non-infectious, inflammatory conditions including systemic autoimmunity, as well as organ-specific pathology. Among the organ-associated disorders, gastrointestinal (GI) manifestations are one of the most intractable. As such, non-infectious inflammatory disorders of the GI tract are clinically challenging as they have protean manifestations, often resembling inflammatory bowel disease (IBD) or celiac disease, are notoriously difficult to treat, and hence are associated with significant morbidity and mortality. Therefore, assessing the pathogenesis and defining appropriate therapeutic approaches for GI disease in patients with CVID and CGD is imperative.