A positive Monospot test misleads: Acute lymphoblastic leukemia presenting as infectious mononucleosis in a 5-year-old.

Epstein-Barr virus (EBV) infection commonly presents as infectious mononucleosis and is frequently evaluated in primary care. Clinical features of EBV infection may overlap with hematologic malignancies, and heterophile antibody (Monospot) testing, while convenient, is not fully specific and may yield false-positive results. We report a 5-year-old previously healthy female who presented with fever, malaise, facial swelling, lymphadenopathy, and hepatosplenomegaly. Initial laboratory evaluation demonstrated anemia, thrombocytopenia, and leukocytosis. A heterophile antibody test was positive, suggesting infectious mononucleosis; however, EBV polymerase chain reaction testing was negative. Progressive cytopenias and markedly elevated tumor lysis markers prompted hematologic evaluation. Peripheral smear and flow cytometry confirmed precursor B-cell acute lymphoblastic leukemia (ALL). Conclusion: A positive Monospot test does not exclude malignancy. Persistent cytopenias, organomegaly, or biochemical features inconsistent with uncomplicated viral illness should prompt reconsideration of the diagnosis and early hematologic evaluation. Recognition of EBV-like presentations of ALL is critical in primary care to avoid delayed diagnosis.