This study examined the resistance of H. pylori to the anti-microbial agent MTZ and specifically focused on the contribution of the rdxA and frxA genes to MTZ resistance. Five MTZ-sensitive and five MTZ- resistant H. pylori strains were obtained from the clinical isolates. Analysis of the deduced RdxA and FrxA amino-acid sequences of these isolates revealed various mutations. To directly evaluate the contribu- tion of these specific rdxA mutations to MTZ resistance, we intro- duced these rdxA variants into G27 while inactivating its own rdxA gene. Our results show that (i) premature truncation of frxA alone is not sufficient to cause MTZ resistance in H. pylori, but has the capacity to enhance MTZ resistance in H. pylori containing a deficient rdxA; (ii) introduction of an inactivated rdxA (non-functional pre- mature truncation) is sufficient to confer MTZ resistance to G27 (normally MTZ sensitive); (iii) introduction of the missense-mutated rdxA alleles (6–9 amino-acid substitutions each) does not result in MTZ resistance; (iv) three high MTZ-resistant isolates (MIC, X256 mg ml