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Helicobacter pylori (H. pylori) eradication rates with omeperazole/amoxicillin range from 0-90%. The best regimen for retreatment after failure of omeprazole/amoxicillin has not been established so far. The aim of this prospective study was to evaluate the efficacy of triple therapy with bismuth, tetracycline and ornidazole in eradicating H. pylori after failure of omeprazole/amoxicillin. 79 duodenal ulcer patients with H. pylori infection were treated with oral omeprazole (40 mg bid) and amoxicillin solute (750 mg tid) for 10 days. Eradication rate was 28/79 (35%) and was distinctly lower in smokers (> 10 cigarettes/day) vs nonsmokers (10/49 [20%] vs 18/30 [60%], p < 0.001). 37 patients with persistent H. pylori infection in whom omeprazole/amoxicillin had failed agreed to retreatment with triple therapy. Persistence of H. pylori was confirmed by histology (3 antral and 2 gastric body biopsies; H&E, Giemsa), urease test (CLO) and/or H. pylori culture. Patients smoking > 10 cigarettes/day were classified as smokers. Retreatment consisted of oral bismuth-subcitrate 4 x 120 mg/d for 28 days (day 1-28), tetracycline 4 x 500 mg/d and ornidazole 3 x 500 mg/d for 10 days (day 1-10). Control endoscopy was done 30 days after the end of treatment. Criteria for H. pylori eradication was negative urease test, culture and histology. 34/37 patients (6 females/28 males; 39 [23-64] years) completed the study (24/34 smokers, 10/34 nonsmokers). 3/37 patients dropped out because of side effects (n = 1) or incompliance (n = 2). H. pylori subcultures for resistance testing were possible in 32/34 patients: H. pylori was metronidazole-sensitive in 11/32 (1 female, 10 males; 38 [24-55] years; 9 smokers, 2 nonsmokers) and metronidazole-resistant (minimal inhibitory concentration for metronidazole > 8 mg/ml) in 21/32 (5 females, 16 males; 40 [23-64] years; 13 smokers, 8 nonsmokers). The overall H. pylori eradication rate of the triple therapy was 27/34 (79%). H. pylori was eradicated in 19/24 (79%) smokers and in 8/10 (80%) nonsmokers. Eradication rate for metronidazole-sensitive H. pylori was 11/11 (100%) vs 14/21 (67%) for metronidazole-resistant H. pylori (p = 0.012). Triple therapy is effective and safe in eradicating H. pylori in patients after failure of omeprazole/amoxicillin. Smoking had no negative effect on the eradication rate of the triple therapy after failure of omeprazole/amoxicillin. Eradication failures were due to metronidazole-resistance.