A large pleural effusion causing cardiac tamponade physiology and severe hemodynamic compromise is an uncommon event. We report a case of a 53-year-old woman with severe hypothyroidism presenting with myxedema coma and refractory shock. Her hemodynamic status failed to respond to fluid resuscitation and vasopressors. A transthoracic echocardiogram and chest radiograph demonstrated a pericardial fluid accumulation associated with a large left-sided pleural effusion. Thoracostomy tube insertion resulted in prompt improvement of the patient's hemodynamic status. Our finding demonstrates that a large pleural effusion may play an important role in cardiac tamponade physiology.