Triple therapy with a proton pump inhibitor plus two antibiotics is recently standard regimen for treatment of H. pylori infection. However, the agents that are used for H. pylori eradication are not always limited to drugs whose primary use is as an antimicrobial agent. Anti-H. pylori activity has been reported for nontraditional antimicrobials such as proton pump inhibitors, bismuth compounds, mucosal defensive agents, and some other agents. Proton pump inhibitors and their acid-activated derivatives have significant activities against H. pylori, potent inhibitors of urease, proton motive force, and ATPase of H. pylori. Some bismuth compounds and compound of a mixture of ranitidine hydrochloride and bismuth citrate were shown to inhibit the growth of H. pylori in vitro, to eradicate H. pylori in vivo, and to decrease the development of H. pylori secondary resistance to antibiotics. The mechanism of bactericidal action of bismuth compounds has not been clear. Mucosal defensive agents that enhance defense factors of gastro-duodenal mucosa are locally acting anti-ulcer drugs. Each mucosal defensive agent was found to have direct or indirect different activities against H. pylori in vitro. Though studies attempting to improve the eradication rate by the addition of mucosal defensive agents to conventional therapy have been tried, additive effects of these agents were equivocal. Therapeutic approaches with other agents such as Lactobacillus, lactoferrin, and dietary constituents to cure H. pylori infection are under investigation. Non-traditional antimicrobials by them selves are unable to cure H. pylori infection in spite of anti-H. pylori activities. Studies are needed to establish the clinical utility of non-traditional antimicrobial agents in prevention and eradication of H. pylori infection since eradication of antibiotic resistance H. pylori would become a difficult problem.