We report a case of a very premature infant who died on day 17 of life because of clinically unsuspected cardiac tamponade due to a pericardial effusion with no gross or microscopic features of myocardial inflammation or perforation. The pericardial effusion probably accumulated for 8 days prior to his death, as evidenced by chest X-ray films. The only relevant microscopic finding was a prominent pericardial and myocardial interstitial edema. Although Staphylococcus epidermidis line sepsis, central venous catheter trauma, hypoalbuminemia, anemia, and heart failure could be possible contributory factors, no definitive cause of the pericardial effusion was found and the etiology of this condition remains obscure.