Proton pump inhibitor-based triple regimens fail to cure Helicobacter pylori infection in at least 10-23% of treated patients. Re-treatment strategies after initial failure remain poorly defined. Of the factors leading to eradication failure, patients' compliance, gender, primary resistance to clarithromycin and metronidazole, and intragastric bacterial load appear to be the most important in determining treatment outcome. Empirical re-treatment should depend mainly upon the antibiotics initially used, as re-administration of the same compound (namely, metronidazole and clarithromycin) is not recommended. Quadruple therapy is usually suggested in this situation, but there is some reluctance to use it in clinical practice on account of the high number of tablets to be taken and concern about side-effects. The use of ranitidine bismuth citrate instead of a proton pump inhibitor plus a bismuth compound in triple second-line regimens has recently proven to be highly effective. Finally, rifabutin-based triple therapies have been shown to be a promising rescue strategy in patients who have failed two or more eradication attempts.