OBJECTIVE: The most effective combination therapy to eradicate Helicobacter pylori has not yet been found. The perfect combination would be effective, relatively free of side effects, and easy to comply with. We studied a 14-day course of three medications taken twice daily by H. pylori-infected patients who were enrolled in the outpatient Veterans Affairs (VA) clinics. The two major objectives were 1) to determine the effectiveness of the combination therapy and 2) to determine the compliance of patients in a VA population. METHODS: Fifty-two male patients were identified with H. pylori infection by positive CLO (Rapid Urease Test) test, positive Giemsa stain, or positive serology. Active infection was confirmed by a positive 13C urea breath test (UBT). Patients were treated for 14 days with open-label triple-combination therapy of ranitidine bismuth citrate (RBC; 400 mg b.i.d.), amoxicillin (1000 mg b.i.d.), and clarithromycin (500 mg b.i.d.). Successful eradication of H. pylori was confirmed by repeat UBT at 6-8 wk after the final dose of therapy. RESULTS: Of the 52 enrolled patients, 49 (94.2%) met the criteria for successful completion of the study (per protocol analysis based on compliance with at least 80% of medication and performance of both UBTs). Of the three patients who did not successfully complete, one was cured (after 6 days of treatment), and two remained infected (after 3 days and 9 days of treatment). Of the 49 completed patients, 45 (91.8%) were cured, and four remained infected. Overall, regardless of compliance (intent-to-treat analysis), 46 of the 52 (88.4%) patients had documented cure of H. pylori infection as determined by the posttreatment UBT. By 3 yr after H. pylori eradication, two of 15 (13.3%) patients who were not on baseline medications had developed the need for antisecretory therapy, but 18 of 31 (58.1%) who were on baseline medications were able to stop therapy. Thus, at 3 yr, successful H. pylori eradication decreased the need for antisecretory therapy from 67.4% of the H. pylori-infected population to 43% of the H. pylori-eradicated population. The effect of H. pylori eradication in improving symptoms at 3 yr was statistically significant in both the ulcer population and the nonulcer population. Adverse events were mild, and included diarrhea (26 patients), bad taste in mouth (24 patients), nausea/upset stomach (nine patients), and headache (two patients). The diarrhea was self-limiting in 25 of the 26 patients. Only two patients discontinued medication because of adverse events. CONCLUSION: The RBC/amoxicillin/clarithromycin combination was, in our VA population, an easily complied with, highly effective, and safe triple therapy with a 90% H. pylori eradication rate. Successful eradication of H. pylori leads to a dramatic decrease in upper-gut symptoms and decreased need for antisecretory therapy.