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Celiac disease is an immune-mediated disorder triggered by hypersensitivity to gluten occurring in genetically susceptible individuals. A high-index of suspicion is needed for diagnosis as patients can be asymptomatic or present with atypical symptoms or extra-intestinal manifestations. Typical 18F-Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET)/Computed Tomography (CT) gastrointestinal manifestations of celiac disease include increased multifocal or diffuse jejunal and ileal uptake; focal duodenal uptake is less common. Splenomegaly with increased splenic FDG uptake is also uncommon in celiac disease in the absence of portal hypertension; small-sized spleen and functional hyposplenism are more typical. We report a case of celiac disease diagnosed after PET/CT showed FDG uptake in the duodenum and enlarged spleen. Follow-up after gluten-free diet showed complete metabolic resolution and regression of splenomegaly. The combination of focal bowel and splenic uptake is unusual in celiac disease and may be mistaken for a lymphoproliferative disorder. Awareness of this entity may avoid misdiagnosis and guide appropriate management. [ABSTRACT FROM AUTHOR]