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Purpose: Despite improvements in neonatal intensive care, the outcomes of extremely-low-birth-weight infants (ELBWIs) with surgical diseases remain to be improved. We started administering enteral miconazole (MCZ) to ELBWIs from 2002 to prevent fungal infection. Since then, the incidence of intestinal perforation has significantly decreased. We investigated this prophylactic effect of MCZ against necrotizing enterocolitis (NEC) and focal intestinal perforation (FIP) and explored a new prophylactic concept against intestinal perforation. Methods: We designed a historical cohort study to evaluate the effect of MCZ for intestinal perforation in ELBWIs who underwent treatment in our neonatal intensive-care unit between January 1998 and December 2005. We divided these cases into two groups: the Pre-MCZ group and the Post-MCZ group. We compared the morbidity, clinical outcomes and pathological features of NEC and FIP. Results: The rate of intestinal perforation with NEC was significantly reduced after the introduction of MCZ (p = 0.007, odds ratio; 3.782, 95% confidence interval; 1.368–12.08). The pathological findings of NEC specimens showed that the accumulation of inflammatory cells was significantly reduced in the Post-MCZ group when compared with the Pre-MCZ group (p < 0.05). Conclusions: The efficacy of the enteral administration of MCZ on intestinal perforation with NEC highlights a new prophylactic concept in the clinical management of ELBWIs. [ABSTRACT FROM AUTHOR]