A 68 year-old woman with diarrhea, anorexia, fatigue, and weight loss was referred for evaluation of refractory sprue. She was diagnosed with celiac disease in 2001 based upon duodenal biopsies showing villous atrophy, increased intraepithelial lymphocytes, and chronic inflammation. Despite initiation of a gluten free diet, her symptoms remained unchanged. The patient underwent 6 upper endoscopies over the following 3 years, all of which showed near total villous atrophy, intraepithelial lymphocytosis, and crypt hyperplasia. In 2003, antigliadin, antiendomysial, and tissue transglutaminase antibody studies were negative; total serum IgA was 6.7mg/dL consistent with IgA deficiency. Treatment of her celiac disease with prednisone and azathioprine yielded little improvement in symptoms. Collagenous sprue and ulcerative ileojejunitis were not found. T-cell studies demonstrated a polyclonal population without T-cell receptor gamma gene rearrangements ruling out enteropathy-associated T-cell lymphoma The patient's past medical history was notable for recurrent sinusitis, urinary tract infections, Salmonella enteritis, and herpes encephalitis. Medications included azathioprine, calcitriol, and lansoprazole. On physical examination, she appeared to be a thin, pale woman with generalized weakness. Abdomen was soft with mild tenderness in the mid-epigastrium and a spleen tip palpable below the costal margin. Skin exam demonstrated scattered ecchymoses; there was no evidence of adenopathy, thyromegaly, or rectal pathology. HLA typing revealed the patient to possess DQ 5,9 and DR 7,16 alleles making celiac disease an unlikely diagnosis. Based upon the patient's history of IgA deficiency, quantitative immunoglobulins were obtained which identified panhypoglobulinemia: IgA<5 mg/dL, IgG<100mg/dL, IgM 4mg/dL. Pathology review confirmed the previous findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. A striking absence of plasma cells within the lamina propria was noted. The histological picture of villous atrophy with absence of plasma cells, in conjunction with panhypoglobulinemia, recurrent infection, splenomegaly, and diarrhea was consistent with a diagnosis of common variable immunodeficiency. This case serves to emphasize the broad differential diagnosis of villous atrophy which includes common variable immunodeficiency. Furthermore, refractory sprue is an uncommon condition and alternative diagnoses should be sought after complications of refractory sprue have been eliminated.