This study investigated the relationship between the drug combinations of the eradication regimens and the prevalence of acquired resistance to clarithromycin. Of 540 patients treated with anti-Helicobacter pylori regimens containing clarithromycin, 55 patients (31 males, mean age, 45.6 years) with failed eradication of H. pylori that was susceptible to clarithromycin before treatment were included. The E test was used to test for susceptibility to clarithromycin (minimum inhibitory concentration (MIC) <1 mg/l). Of the 55 patients, 33 (60.0%) developed clarithromycin resistance after failed eradication. Of the dual therapies, the combination of a proton pump inhibitor (PPI) and clarithromycin resulted in 88.9% (8/9) of the patients acquiring clarithromycic-resistance. With the triple therapies, the percentages of patients acquiring clarithromycin resistant strains after using a PPI+clarithromycin+amoxycillin or a PPI+clarithromycin+metronidazole were 38.7% (12/31) and 90.0% (9/10), respectively (P<0.01). These data suggest that regimens containing amoxycillin may prevent the selection of secondary clarithromycin resistance.