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Pericardial effusions may necessitate placement of a catheter into the pericardial space for continuous drainage. If the effusion material is fibrinous or loculated, drainage may slow or cease over time, allowing reaccumulation. Limited data exist to guide the selection of a fibrinolytic agent and the most appropriate dose. We report the case of a 79-year-old woman with malignant pericardial effusion who responded to intrapericardial administration of tenecteplase to facilitate drainage. The patient received three doses of tenecteplase—15 mg, 7.5 mg, and 7.5 mg—over 3 days, resulting in significant drainage. No adverse effects were noted except for a transient episode of hemodynamically stable atrial fibrillation. Use of fibrinolytic agents to facilitate pericardial drainage may offset the need to repeatedly replace the catheter if flow subsides despite continued presence of fluid in the pericardial space.