Background: Traditional standard triple therapy for Helicobacter pylori infection (PPI-clarithromycin-amoxicillin) can easily be converted to non-bismuth quadruple (concomitant) therapy by the addition of a nitroimidazole twice daily. Aim: To critically review evidence on the role of non-bismuth quadruple therapy (PPI-clarithromycin-amoxicillin-nitroimidazole) in the treatment of H. pylori infection. Methods: Bibliographical searches were performed in MEDLINE and relevant congresses. Results: The first randomised comparison of the non-bismuth quadruple therapy and the sequential (PPI-amoxicillin 5 days plus PPI-clarithromycin-nitroimidazole 5 days) regimens recently concluded that both were similar in terms of efficacy and safety and that the sequential administration protocol may be unnecessarily complex. Several randomised controlled trials (and one meta-analysis) have demonstrated that non-bismuth quadruple therapy is more effective than and is equally well tolerated as standard triple therapy. A meta-analysis of 15 studies (1723 patients) revealed a mean H. pylori cure rate (intention-to-treat) of 90% for non-bismuth quadruple therapy. A tendency towards better results with longer treatments (7-10 days vs. 3-5 days) has been observed, so it seems reasonable to recommend the length of treatment by achieving maximal cure rates (10 days). Clarithromycin resistance may reduce the efficacy of non-bismuth quadruple therapy, although the decrease in eradication rates seems to be far lower than in standard triple therapy. Experience with the non-bismuth quadruple therapy in patients with metronidazole-resistant strains is still very limited. Conclusions: Non-bismuth quadruple (concomitant) therapy appears to be an effective, safe, and well-tolerated alternative to triple therapy and is less complex than sequential therapy. Therefore, this regimen appears well suited for use in settings where the efficacy of triple therapy is unacceptably low. © 2011 Blackwell Publishing Ltd.