Pericardial decompression syndrome (PDS) is a rare and serious complication that follows often-initially-uncomplicated pericardial drainage in patients with pericardial effusion and tamponade physiology. The pathophysiology of PDS is not yet completely understood, although several mechanisms have been postulated. In this report, we present a case of PDS in a 70-year-old male with end-stage renal disease (ESRD) after he underwent a surgical pericardial window for drainage of a moderate pericardial effusion with tamponade physiology. This case provides further evidence that rapid pericardial decompression, notably with pericardiotomy, can lead to acute life-threatening low cardiac output heart failure, particularly in patients with underlying cardiac risk factors. Early recognition, diagnosis, and supportive treatment in the ICU are crucial for improving survival rates in these patients.