Purpose: Helicobacter pylori is an insidious infection with a significant link to gastric carcinoma, lymphoma and peptic ulcer disease and has been designated a WHO class I carcinogen. The prevalence has been estimated at about 70% in developing countries and 30–40% in the United States. Emerging resistance to currently used drugs (eg. metronidazole (28.9%), clarithromycin (10.9%) and amoxicillin (12%)) have become a limiting factor in the success of therapy. Triple therapy with clarithromycin, amoxicillin and a proton pump inhibitor (PPI) has been the gold standard treatment regimen. Rifaximin and levofloxacin have been used individually with good success in various trials as salvage therapy for recurrence of H. pylori. We present our own experience with a novel regimen of rifaximin, omeprazole and levofloxacin as first-line therapy for eradication of H. pylori in the treatment-naïve population. Methods: Patients with dyspeptic symptoms were evaluated by means of upper endoscopy with biopsy and stool antigen testing for H. pylori (Quest Diagnostic Labs, Teterboro, NJ). Stool antigen testing has been proven to be a safe and noninvasive means of detecting H. pylori with high sensitivity and specificity. Twenty patients of diverse ethnic background with stool antigens positive for H. pylori and confirmed histologically were included in this study. Patients with use of a PPI, NSAIDs, ASA or antibiotics in the four weeks preceding detection of H. pylori were excluded. Patients were treated with rifaxamin 400 mg, omeprazole 20 mg and levofloxacin 250 mg, all twice daily, for 10 days. Follow-up stool testing for H. pylori was performed after cessation of omeprazole for a minimum of 2 weeks. Results: Of the twenty patients enrolled that were found to have stool antigen evidence of H. pylori, ten had stools negative for H. pylori on repeat testing after treatment with rifaximin, omeprazole and levofloxacin (50%). Of the twenty patients enrolled, all were able to tolerate the regimen without incident (100%). Conclusions: Our regimen of rifaximin, omeprazole and levofloxacin had a success rate of 50% in the eradication of H. pylori and may be of limited utility as a first line therapy. It is, however, a well-tolerated regimen and may be better suited as a salvage therapy for recurrence of infection or in those patients who are unable to tolerate the current standard regimen. Further larger studies are needed to evaluate the efficacy of this regimen.