Introduction. Pericardial effusion (PCE) and tamponade can cause significant morbidity and mortality in neonates. Such cases have been reported in the literature in various contexts. Case Presentation. A 6-day old neonate with meconium aspiration syndrome and persistent pulmonary hypertension of newborn on high frequency oscillator ventilation and inhaled nitric oxide was referred to our hospital with a large pericardial effusion causing hemodynamic compromise. Prompt pericardiocentesis led to significant improvement in the cardio-respiratory status and removal of the central line prevented the fluid from reaccumulating. Cellular and biochemical analysis aided in the diagnosis of catheter related etiology with possibility of infusate diffusion into the pericardial space. Conclusion. We present this paper to emphasize the importance of recognizing this uncommon but serious complication of central venous catheters in intensive care units. We also discuss the proposed hypothesis for the mechanism of production of PCE.