Currently, the first therapeutic attempt to eradicate Helicobacter pylori fails in one case out of six in intention to treat analysis. The main causes of failure are bad compliance, partly because of side effects that are severe in 1 to 4% of cases, absence of local validation of the treatment scheme, since some differences do exist between regions and countries, primary and secondary resistance of the strain (stable for Imidazole-derivates, but increasing for Macrolides), and, to a lesser extent, smoking and pre-treatment with proton pump inhibitors. Moreover, in routine medicine, inappropriate treatment cocktails are still prescribed, even by gastroenterologists. Obviously, there is a need for careful medical education and information both as far as concerns doctors and patients, for well-designed prescription, based on local experience and the precise previous history of every patient, as well as for continuous monitoring of the bacterial resistance to antibiotics. Culture of the strain is recommended after eradication failure with the classic one-week triple therapy, but if reliable culture and resistance testing are not available, the quadruple therapy as a second-line treatment is, so far, the best choice.