The aim of this study was to evaluate the presence and prevalence of multidrug antibacterial resistance in Helicobacter pylori in Bulgaria from 2005 to 2008. The resistance in 828 untreated adults, 124 treated adults and 105 untreated children was, respectively, 26.5, 50.8 and 16.2% for metronidazole; 18.4, 45.2 and 19% for clarithromycin; 1, 2.4 and 0% for amoxicillin; 4.4, 10.6 and 1.9% for tetracycline; and 9, 14.5 and 5.8% for ciprofloxacin. Triple resistance to the evaluated agents was uncommon and was detected in 1% of the untreated children, 3.5% of the untreated adults and 13.6% of the treated adults. Five H. pylori strains were resistant to amoxicillin, metronidazole and clarithromycin, two of them exhibiting quadruple resistance. Resistance to four of the five antibacterials tested was found in 0.7% of the untreated and 1.8% of the treated adults. The overall level of multidrug resistance in the treated adults (15.4%) was higher than that in the untreated adults (4.2%, P=0.0001) and the untreated children (1%, P=0.0001). The presence of multidrug H. pylori resistance in Bulgaria could be associated with many factors, among them the slightly increasing national use of macrolides, lincosamides and streptogramins and of quinolones since 2000, the significant increase in primary H. pylori clarithromycin resistance, the high tetracycline use between 1994 and 1999, and, in individual cases, the use of azithromycin-based regimens or reuse of nitroimidazoles. In conclusion, for the first time in a European country during the last 5 years, H. pylori strains harbouring a worrying quadruple antibacterial resistance were found in treated as well as in untreated patients. H. pylori susceptibility patterns have a tendency to become unpredictable and should be monitored constantly at both national and global levels.