Even with the current most effective treatment regimens, about 10-20% of patients will fail to eradicate H. pylori infection. Therefore, in designing a treatment strategy we should not focus on the results of primary therapy alone, but also on the final (over-all) eradication rate. The choice of a second-line treatment depends on which treatment was used initially, as retreatment with the same regimen is not recommended. In this respect, the first therapy should not be a regimen that combines clarithromycin and metronidazole in the same regimen, because of the problem of resistance against both antibiotics. Therefore, it seems that performing culture after a first eradication failure is not necessary and assessing H. pylori sensitivity to antibiotics only after failure of the second treatment may be suggested in clinical practice. Different possibilities of empirical treatment are suggested. After failure of proton pump inhibitor (PPI)-amoxicillin-clarithromycin, quadruple therapy has been generally used. More recently, replacing the PPI and the bismuth compound by ranitidine bismuth citrate (RBC) has also achieved good results. After PPI-amoxicillin-nitroimidazole failure, retreatment with PPI-amoxicillin-clarithromycin has proved to be effective. Finally, rifabutin-based rescue therapies have shown to constitute an encouraging strategy for eradication failures, as they are effective for H. pylori strains resistant to antibiotics.