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Aim Necrotising enterocolitis (NEC) is still a disease with high morbidity and mortality. The aim of the study was to analyse retrospectively whether the introduction of a multi‐modal three‐component enteral medication regimen resulted in a change in morbidity and mortality in neonates with NEC. Methods When diagnosis of NEC was established, the following multi‐modal three‐component enteral medication regimen was administered enterally (via nasogastric tube): an antibiotic, an antifungal agent and a probiotic. The primary outcome parameters were intestinal perforation, surgical interventions and mortality during the observational periods. Results In the study period, 2212 patients were admitted to the NICU, out of which 200 (9%) developed NEC. Significantly fewer infants died in the Intervention Group (13 of 104 infants, 13%) compared to the Control Group (38 of 96 infants, 40%) (P = .0001). No infant in the Intervention Group (0%) presented with an intestinal perforation, as compared to 15 infants (16%) within the Control Group (P = .0001). In the Control Group, 21 infants (22%) needed surgical intervention, whereas 0 (0%) infants needed this in the Intervention Group. Conclusion The introduction of an enteral multi‐modal three‐component medication regimen resulted in a significant reduction of mortality and of need for surgical intervention in infants suffering from NEC.