Although survival after the Fontan operation has improved, little is known about the burden of major medical morbidities associated with the modern total cavopulmonary connection (TCPC). A total of 773 consecutive patients who underwent a first Fontan operation at our institution between 1992 and 2009 were retrospectively reviewed. All subjects underwent TCPC (53% lateral tunnel, 47% extracardiac conduit). Median length of follow-up was 5.3 years (interquartile range 1.4 to 11.2), and 30% had follow-up >10 years. Freedom from a composite medical morbidity outcome (protein-losing enteropathy, plastic bronchitis, serious thromboembolic event, or tachyarrhythmia) was 47% at 20 years (95% confidence interval [CI] 38 to 55). Independent risk factors for morbidity included pre-Fontan atrioventricular valve regurgitation (hazard ratio [HR] 1.7, 95% CI 1.2 to 2.4, p = 0.001), pleural drainage >14 days (HR 1.5, 95% CI 1.01 to 2.2, p = 0.04), and longer cross-clamp time (HR 1.2 per 10 minutes, 95% CI 1.06 to 1.3, p = 0.004) at the time of TCPC. Surgical era, Fontan type, and ventricular morphology were not associated with the composite outcome. Presence of Fontan-associated morbidity was associated with a 36-fold increase in the risk of subsequent Fontan takedown, heart transplantation, or death (95% CI 17 to 76, p <0.001). For patients without any component of the composite outcome, freedom from Fontan failure was 98% at 20 years (95% CI 96 to 99). Medical morbidities after TCPC are common and significantly reduce the longevity of the Fontan circulation. However, for those patients who remain free from the composite morbidity outcome, 20-year survival with intact Fontan circulation is encouraging.