Triple therapy is commonly used for the treatment of Helicobacter pylori infection. We determined risk factors associated with its failure in compliant Patients focusing on H. pylori density, virulence marker and 23S ribosomal RNA (rRNA) point mutations associated with clarithromycin resistance. H. pylori infection was diagnosed by (14)C urea breath test ((14)C UBT) and rapid urease test or histology. Triple therapy with esomeprazole 20 mg b.i.d., amoxicillin 1 g b.i.d. and clarithromycin 500 mg b.i.d. was prescribed for 10 days. 14C UBT was repeated 4 weeks after treatment. In total, 111 Patients [69 (62%) males] with a mean age of 46 +/- 16 years were enrolled. The mean age of treatment failure was 39 +/- 14 years compared to 48 +/- 16 years with eradication (P=0.002). Treatment failure was associated with younger mean age, point mutations in the 23S rRNA gene of H. pylori and vacA s1a and m1 when associated with cagA negativity.