This study was designed to investigate the impact of postoperative coronary sinus drainage pressure on coronary flow reserve (CFR) assessed by Doppler guidewire in patients long term after Fontan operation. Twenty-nine patients (median age, 17.4 years female, 11) at a median of 10.6 years after Fontan operation were examined with intracoronary Doppler guidewire during cardiac catheterization. Fourteen patients had coronary sinus (CS) drainage to the systemic venous atrium and 15 patients had CS drainage to the pulmonary venous atrium after Fontan operation. Median CS drainage pressure was significantly higher in systemic venous CS drainage compared to pulmonary venous CS drainage (11 vs 5 mmHg, p < 0.0001). Median CFR values for the right and left coronary artery did not differ significantly with respect to CS drainage. There was a positive correlation between coronary flow reserve and pulmonary arteriolar resistance (p < 0.05) in multivariate regression analysis. The site of coronary drainage into the systemic atrium or the pulmonary venous atrium did not significantly affect CFR. Our data do not support a surgical strategy of elective redirection of coronary sinus blood to a low-pressure compartment but support an early staged approach. The positive correlation between CFR and pulmonary resistance demands further evaluation.