Infants with critical congenital heart disease, especially patients with a single-ventricle (SV) physiology, are at increased risk for the development of necrotizing enterocolitis (NEC). Decreased splanchnic oxygen delivery may contribute to the development of NEC and may be detected by regional oximetry (rSO2) via splanchnic near-infrared spectroscopy (NIRS). This prospective study enrolled 64 neonates undergoing biventricular (BV) repair or SV palliation for CHD and monitored postoperative splanchnic rSO2 before and during initiation of enteral feedings to determine whether changes in rSO2 are associated with risk of NEC. Suspected or proven NEC was observed in 32 % (11/34) of the SV subjects and 0 % (0/30) of the BV subjects (p = 0.001). Compared with the BV subjects, the SV palliated subjects had significantly lower splanchnic rSO2 before and during initiation of enteral feedings, but the groups showed no difference after correction for lower pulse oximetry (SpO2) in the SV group. The clinical parameters were similar among the SV subjects with and without NEC except for cardiopulmonary bypass times, which were longer for the patients who experienced NEC (126 vs 85 min; p = 0.03). No difference was observed in splanchnic rSO2 or in the SpO2-rSO2 difference between the SV subjects with and without NEC. Compared with the patients who had suspected or no NEC, the subjects with proven NEC had a lower average splanchnic rSO2 (32.6 vs 47.0 %; p = 0.05), more time with rSO2 less than 30 % (48.8 vs 6.7 %; p = 0.04) at one-fourth-volume feeds, and more time with SpO2-rSO2 exceeding 50 % (33.3 vs 0 %; p = 0.03) before feeds were initiated. These data suggest that splanchnic NIRS may be a useful tool for assessing risk of NEC, especially in patients with an SV physiology.