H. pylori eradication is a challenge in patients allergic to penicillin, both first-line and failures of prior therapy. We aimed to assess the eradication rate of H. pylori in patients allergic to penicillin, first-line and failures of prior therapy, the efficacy of healing of active duodenal ulcer disease (DUD) and erosive gastritis, and the safety and tolerability of the combination. Twenty patients with documented allergy to penicillin, DUD, and H. pylori infection, 17 (85%) for first-line treatment and 3 (15%) prior therapy failures, were given a 10-day regimen of esomeprazole, 40 mg qid, tetracycline, 500 mg qid, and metronidazole, 500 mg qid. Baseline and follow-up panendoscopy > or =30 days after end of treatment was performed for rapid urease test (Clotest), and four site biopsies for H. pylori, and to document endoscopic peptic ulcer disease. All adverse events during treatment were documented. Eradication rates by intention to treat (ITT) were 85% for first-line treatment and 100% for failures. Seventy percent of all cases had a normal endoscopy at follow-up, and 85 and 100% of patients had healed erosive gastritis and DUD, respectively, from baseline. There were histological improvements in most patients. A high eradication rate was obtained even in patients who had a shorter duration of treatment. The combination was well tolerated. A combination of esomeprazole, tetracycline, and metronidazole is effective for eradication of H. pylori in patients allergic to penicillin, for both first-line treatment and failures of prior treatment.