Plaunotol, a cytoprotective anti-ulcer agent, has antibacterial activity against Helicobacter pylori. The purpose of the present study was to investigate the effect of plaunotol when combined with clarithromycin or amoxicillin against H. pylori. When combined with clarithro- mycin, plaunotol showed synergic activity against 11 of 14 strains, and additive activity against the other three strains, by chequerboard titration. When combined with amoxicillin, plaunotol showed additive activity against 10 of 14 strains. No antagonistic effects were seen against any ofthe strains tested.The interactions betweenplaunotolandeither clarithromycinor amoxicillin were determined by time–kill assay against the Sydney Strain (strain SS1) of H. pylori.The combination of plaunotol with clarithromycin showed synergic activity and with amoxicillin showed additive activity. In a C57BL/6 mouse gastritis model infected with H. pylori SS1, the plaunotol–clarithromycin and plaunotol–amoxicillin combinations both exhibited synergic effects, which allowed the effective dose of clarithromycin to be reduced when co-administered with plaunotol. These results suggest that plaunotol may have a useful role in combination with anti-H. pyloridrugs in the treatment of H. pylori-associated diseases.