The occurrence of refractory Helicobacter pylori infection is increasing. When the bacteria are not eradicated it means that the antibiotics have not reached the gastric mucosa at a sufficient concentration and over a sufficient time lapse to kill them. The main reasons for this are poor patient compliance, resistant bacteria, low gastric pH and a high bacterial load. Therefore, when administering a new treatment, it is important to choose antibiotics which do not face resistance problems and which increase the dosage of antisecretory drugs and the duration of treatment and, if possible, to add a topical agent such as bismuth salt. The recommended empirical strategy is to prescribe quadruple therapy or, alternatively, 2-week triple therapy including amoxicillin-metronidazole, tetracycline-metronidazole or amoxicillin-rifabutin. However, when H. pylori is susceptible, clarithromycin can still be used. In the case of a high level of metronidazole resistance, furazolidone can be employed. In each case, it is important to ensure good patient compliance, and counselling is helpful in this regard. However, the best approach remains the prevention of refractory H. pylori infection and, for this purpose, antimicrobial susceptibility testing before first-line therapy is important and should be encouraged.