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ABSTRACTHelicobacter pyloriis a globally important and genetically diverse gastric pathogen that infects most people in developing countries. Eradication efforts are complicated by antibiotic resistance, which varies in frequency geographically. There are very few data on resistance in African strains. Sixty-four Gambian H. pyloristrains were tested for antibiotic susceptibility. The role of rdxAin metronidazole (Mtz) susceptibility was tested by DNA transformation and sequencing; RdxA protein variants were interpreted in terms of RdxA structure. Forty-four strains (69%) were resistant to at least 8 μg of Mtz/ml. All six strains from infants, but only 24% of strains from adults, were sensitive (P= 0.0031). Representative Mtz-resistant (Mtzr) strains were rendered Mtz susceptible (Mtzs) by transformation with a functional rdxAgene; conversely, Mtzsstrains were rendered Mtzrby rdxAinactivation. Many mutations were found by Gambian H. pylorirdxAsequencing; mutations that probably inactivated rdxAin Mtzrstrains were identified and explained using RdxA protein's structure. All of the strains were sensitive to clarithromycin and erythromycin. Amoxicillin and tetracycline resistance was rare. Sequence analysis indicated that most tetracycline resistance, when found, was not due to 16S rRNA gene mutations. These data suggest caution in the use of Mtz-based therapies in The Gambia. The increasing use of macrolides against respiratory infections in The Gambia calls for continued antibiotic susceptibility monitoring. The rich variety of rdxAmutations that we found will be useful in further structure-function studies of RdxA, the enzyme responsible for Mtz susceptibility in this important pathogen.