Background: The specific etiology of spontaneous intestinal perforation (SIP) and necrotizing enterocolitis (NEC) remains elusive. Both can present acutely without antecedent signs and can be difficult to differentiate. Neonatal nucleated red blood cell (NRBC) counts are part of the routine admission and serial CBCs drawn on premature neonates. Elevated NRBC counts could represent relative intrauterine hypoxemia, a possible risk factor for the development of SIP or NEC. Methods: We compared premature neonates with SIP to premature neonates with NEC and controls, matched gestational age (GA) and birth weight (BW). Kruskal-Wallis, Chi-Square, or Fisher's exact tests and univariate and multivariate nominal logistic regression models were used to estimate the association of baseline NRBC. Median times to SIP and NEC were calculated using the Kaplan-Meier method. All analyses were performed with SAS 9.4. Results: Male sex (72.5%), lower GA [Median (Q1, Q3): 25.1 (23.8, 28)], and lower BW [Median (Q1, Q3): 690 g (585, 1072)] had the highest incidence of SIP compared to NEC or controls. Increased baseline NRBC was associated with lower odds of developing NEC compared to controls [Median (Q1, Q3): 9 (5, 29) vs 19 (10, 51); OR (CI) 0.70 (0.55, 0.89), p-value = 0.0033]. Increased baseline NRBC was associated with higher odds of developing SIP compared to NEC [Median (Q1, Q3): 9 (5, 29) vs 19 (10, 51); OR (CI) 1.61 (1.18, 2.20) p-value = 0.0027]. There were no significant differences between intrauterine growth restriction (IUGR), maternal hypertension, chorioamnionitis, multiple births, or depressed APGAR scores in all three groups. NRBC for SIP neonates remained significantly higher at the day of life (DOL) 1-3 compared to other groups [Median (Q1, Q3): 23 (6, 93), p-value = 0.0020]. The percentage of patients with NRBC >4, remained elevated for patients with SIP as late as week three (p = 0.0023). Conclusion: ELBW, male sex, and elevated baseline NRBC were significantly associated with the risk of developing SIP compared to NEC or controls. NRBC remained significantly elevated on DOL 1-3, compared to NEC or controls. Between the groups, there were no significant differences in perinatal stressors.