Introduction: Treatment of Helicobacter pylori gastritis remains a challenge despite the availability of effective therapies, with eradication rates of 80 %. Our aim was to investigate the efficacy of quadruple therapy in children with H. pylori gastritis when two courses of primary triple anti- H. pylori therapy had failed. Methods: Charts of children with proven H. pylori gastritis as diagnosed with two of the following three criteria: namely positive CLO test, culture, and / or histology were reviewed. We selected only those who had received two courses of triple therapy with either Omeprazole or Lansoprazole and a combination of two of the following antibiotics: Amoxicillin 40 mg / kg / d, max 1g bid; Clarithromycin 250 mg bid in children <10 years, and 500 mg bid in children > 10 years; Metronidazole 20 mg / kg / d, max 500 mg bid; Tetracycline 50 mg / kg / d, max 1 g / d. Results: Eighteen patients met the criteria for quadruple therapy. Age range was 4–18 years, mean 12.8 years. 11 females / 7 males, 12 African American, 3 Caucasian, 3 Hispanic. This group received quadruple therapy of a PPI in addition to two of the above mentioned antibiotics based on antibiotic susceptibilities, as well as Pepto-Bismol bid for two weeks. Ten patients of these have been evaluated with follow-up endoscopies to assess eradication; 7/10 were cured with complete eradication of H. pylori based on follow-up endoscopy, CLO, and culture; and 3/10 showed persistence of infection on repeat endoscopy, (although these particular patients had more than two failures of triple therapy in the past despite the H. pylori strain being susceptible to the antibiotics chosen, therefore a question of compliance arises). Repeat endoscopy is pending in the rest 8 patients; however, follow-up serology has shown a trend for decreasing serum titers of H. pylori IgG levels. Conclusion: We conclude rescue therapy with four drugs can be effective in those who failed to eradicate with triple therapy; however, a multitude of factors play a role in the outcome of H. pylori eradication or persistence, as antimicrobial susceptibility, patient compliance, and inherent qualities in the H. pylori strain itself.