Tyrosine kinase inhibitors (TKIs) are the first-line treatment for patients with chronic myelogenous leukemia (CML). Serositis, including pleural and pericardial effusions, is a frequent adverse event with some TKIs while less frequent with others. We present a case of a 76-year-old woman with CML on nilotinib who presented with progressive fatigue and was eventually found to have cardiac tamponade from a large pericardial effusion attributed to nilotinib. The patient required urgent therapeutic pericardiocentesis and switching of TKIs from nilotinib to bosutinib.

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