Background: The pathogenesis of inflammatory bowel disease (IBD) is complex and involves the contribution of genetic and environmental factors. Many patients with very early onset IBD are difficult to treat. The current antibiotic medication that targets gram-negative and anaerobic bacteria provides only moderate efficacy in subsets of patients with IBD. Methods: We report a case series of 5 children with a mean age of 1.6 years (range 6 months to 2.7 years) during IBD onset, who were previously refractory to standard treatments and who received oral vancomycin with or without gentamicin. Results: Four out of 5 children demonstrated substantial therapeutic effect, and the effect was sustained in 3 children over a follow-up period of 12-33 months. Conclusion: Our findings are consistent with model systems and suggest that randomized trials are required to establish whether a change in therapeutic paradigm, that is, targeting gram-positive bacteria with nonabsorbable antibiotics, may have therapeutic benefits.