Protein-losing enteropathy (PLE) is a complex disorder characterized by enteric protein loss and often is associated with cardiovascular abnormalities, particularly those with elevated central venous pressure. The Fontan operation is a surgical procedure used to palliate patients with a functional single ventricle. Although the Fontan operation eliminates cyanosis and decreases the workload of the functionally single ventricle, it also elevates central venous pressure. This can result in hepatic and enteric congestion as well as PLE. Despite the universal elevation in central venous pressure, only a fraction of patients who have had a Fontan operation develop PLE. However, PLE is associated with significant morbidity and mortality. Presenting signs and symptoms of PLE include abdominal bloating, diarrhea, edema, pleural effusions, ascites, and failure to thrive. In this review, the authors discuss the diagnosis and prevalence of PLE after the Fontan operation and review currently available therapeutic strategies.