Background: Hypogammaglobulinemia has been reported after cardiac surgery and may be associated with adverse outcomes. We sought to define baseline immunoglobulin (Ig) concentration in neonates and infants with congenital heart disease, determine their course after cardiopulmonary bypass (CPB), and determine if post-CPB hypogammaglobulinemia was associated with increased morbidity. Methods: This was a single-center, retrospective analysis of infants who underwent cardiac surgery with CPB between June 2010 and December 2011. The Ig concentration was obtained from banked plasma of 47 patients from a prior study (pre-CPB, immediately post-CPB, and 24 and 48 hours post-CPB). In addition, any Ig levels drawn for clinical purposes after CPB were included. Ig levels were excluded if drawn after chylothorax diagnosis or intravenous IgG administration. Results: The median age was 7 days. Preoperative Ig concentration was similar to that described in healthy children. IgG level decreased to less than 50% of preoperative concentration by 24-hour post-CPB and failed to recover by 7 days. Of 47 patients, 25 (53%) had low IgG (<248 mg/dL) after CPB. Despite no difference in demographics or risk factors between patients with low and normal IgG, low IgG patients had more positive fluid balance at 24 hours and increased proinflammatory plasma cytokine levels, duration of mechanical ventilation, and cardiac intensive care unit length of stay. In addition, low IgG patients had an increased incidence of postoperative infections (40% vs 14%; P =.056). Conclusions: Hypogammaglobulinemia occurs in half of infants after CPB. Its association with fluid overload and increased inflammatory cytokines suggests it may result from capillary leak. Postoperative hypogammaglobulinemia is associated with increased morbidity, including more secondary infections. Copyright © 2014 by The American Association for Thoracic Surgery.