Background Acute lymphoblastic leukemia (ALL) with a clinical presentation of cardiac tamponade and the presence of blasts in the pericardial fluid is all uncommon event. A cytopathologist needs to adopt a cautious interpretive approach while dealing with a lymphoid-rich pericardial effusion in order to prevent a false negative diagnosis. Case A 27-year-old male presented with breathlessness, ascites, bilateral pedal and fiver. He had mild hepatomegaly. On detailed clinical examination, a diagnosis of anemia with cardiac tamponade was made. Cytology of pericardial fluid revealed a large number of lymphoid cells in a hemorrhagic background that, under low magnification, closely, resembled mature lymphocytes. However, a careful examination of May-Griinwald-Giemsa-stained cytologic smears, under an oil immersion objective (x 1,000), showed atypical lymphoid cells having blastoid morphology. Rare lymphoid cells displayed a "hand mirror" appearance. A hematologic workup was carried out to exclude leukemial/lymphoma. Complete blood count revealed pancytopenia with abnormal lymphoid cells. Bone marrow showed replacement by 90% lymphoblasts exhibiting periodic acid-Schiff stain, CD3 and terminal deoxynucleotidyl transferase positivity. A diagnosis of T-cell acute lymphoblastic leukemia (FAB L1) was offered, and the patient was started on a remission and induction regimen. However, be had a rapid downhill course and died of cardiorespiratory arrest. Conclusion Both clinicians and cytopathologists need to be aware of rare instances in which ALL may present with a pericardial effusion as all initial manifestation. The abnormal lymphoid cells found in the pericardial fluid in such situations need to be interpreted cautiously, as their presence is of clinical significance. (Acta Cytol 2009;53:337-340)