BACKGROUND: Helicobacter pylori is one of the most common causes of bacterial infection in humans. Resistance of this infection to conventional therapies has suggested the role of a biofilm-growing bacterium, which is recalcitrant to many antimicrobial agents. AIM: To review the current knowledge on biofilm formation by H. pylori and to discuss the implications of this behaviour in the context of human infections and their treatment. RESULTS: Scanning electron microscopy analysis of gastric biopsies of infected patients demonstrated that H. pylori forms biofilm on the gastric mucosa epithelium. Adaptation to the biofilm environment may produce many persister cells, namely dormant cells, which are highly tolerant to antimicrobials that could account for the recalcitrance of H. pylori infections in vivo. Resistant H. pylori infection has become increasingly common with triple or quadruple therapy, even in the presence of H. pylori strains susceptible to all antibiotics. The mucolytic and thiol-containing antioxidant N-acetylcysteine, associated with antibiotics, was successfully used in clinic for therapy of patients with chronic respiratory tract infections. Consistently, N-acetylcysteine treatment prior to starting antibiotic therapy allowed the disappearance of gastric biofilm in all patients in whom H. pylori was eradicated. CONCLUSION: Effective strategies targeting H. pylori biofilm infections are possible, through the use of substances degrading components of the biofilm.