BACKGROUND: Interferon regulatory factor-2 binding protein-2 (IRF2BP2) is a transcription factor that plays an important role in regulating immune pathways, angiogenesis, apoptosis, and cell differentiation. Defects in this gene have been implicated in immunodeficiency. OBJECTIVE: To deepen the understanding of the clinical implications of IRF2BP2 variants, we sought to clinically characterize and functionally test thirty-four individuals with IRF2BP2 variants. METHODS: We collected 34 subjects across 18 families with mutations in IRF2BP2. Records were abstracted for clinical phenotypes. Functional testing was performed on peripheral blood mononuclear cells (PBMCs). Nuclear factor of activated T cells (NFAT) luciferase gene reporter constructs and quantitative cDNA determinations were used to evaluate repressor activity associated with ectopic expression of various IRF2BP2 mutant constructs in Jurkat cells. RESULTS: Most subjects had immunodeficiency (91%, n = 30/33) with variable gastrointestinal (65%, n= 20/31) and inflammatory or autoimmune features (57%, n=17/30), including chronic abdominal pain, colitis, diarrhea, constipation, vitiligo, alopecia, and migratory rashes. There was a reduced frequency of memory B-cells with poor immunoglobulin production and reduced calcium flux in response to B-cell receptor stimuli. PBMCs had increased apoptosis in vitro compared to healthy controls. Impaired IRF2BP2 repression of NFAT activation was observed using patient-derived mutant IRF2BP2 constructs compared to wild-type. Similarly, TNF-α transcript levels were higher using patient-derived mutations compared to wild-type IRF2BP2 constructs. CONCLUSIONS: IRF2BP2 deficiency causes a complex immunodeficiency including gastrointestinal and inflammatory disorders as well as impaired B-cell maturation. Impaired repression of the NFAT pathway appears to enhance proinflammatory signaling through proinflammatory cytokine expression.