Very low birth weight (VLBW) neonates experience various problems, including meconium-related ileus (MRI). This study investigated the risk factors of MRI and surgical MRI in VLBW infants. VLBW neonates admitted to the Neonatal Intensive Care Unit of Seoul National University Children’s Hospital from October 2002 to September 2016 were included in the study. The diagnostic criteria for MRI were a decreased frequency of defecation with intolerable feeding, vomiting, and increased gastric residue (>50%); meconium-filled bowel dilatation in an imaging study; and no evidence of necrotizing enteritis or spontaneous intestinal perforation. Medical MRIs and surgical MRIs were managed through conventional treatment and surgical intervention. Of 1543 neonates, 69 and 1474 were in the patient and control groups, respectively. The risk factors for MRI include low birth weight (BW), cesarean section delivery, fetal distress, maternal diabetes, maternal hypertension, and maternal steroid use. Low BW and fetal distress were independent risk factors for MRI. Compared to the medical MRI group (n = 44), the risk factors for surgical MRI (n = 25) included males, younger gestational age, low BW, and meconium located at the small bowel. Male gender and low BW were independent risk factors for surgical MRI. Low BW and fetal distress were independent risk factors for MRI and male gender and low BW were independent risk factors for surgical MRI. In VLBW neonates, careful attention to the risk factors for MRI could minimize or avoid surgical interventions.