Background & Aims: H. pylori eradication is strongly affected by various factors, including the ongoing antibiotic resistance. We describe a “real life” scenario in patients managed for H. pylori-related conditions, living in a southern Italian region (Apulia), an area with clarithromycin resistance >15%.Methods: 2,224 subjects were studied in two tertiary referral centers in Apulia. Analyses included: reason for referral, H. pylori infection rates (13C-urea breath test – UBT or upper endoscopy), and eradication rates following distinct regimens previously prescribed or prospectively prescribed (such as the bismuth-based quadruple therapy Pylera®, recently marketed in Italy).Results. Over 80% of the patients were referred by family physicians (60% naïve subjects). The overall infection rate was 32.5% and it was similar in asymptomatic patients (31.1%) or with H. pylori-related symptoms/clinical conditions (34.3%). In the 987 H. pylori+ve patients receiving therapy, the overall eradication rate was 80.2% (ITT). Observed eradication rate varied greatly across different regimens: 57.1% (2nd line levofloxacin), 59.6% (unconventional), 70.7% (7-day triple), 73.2% (7-day undefined), 89% (10-day sequential) and 96.9% (ITT, 10 day Pylera®, 1st to 5th line regimens given to 227 patients).Conclusions. A heterogeneous “real life” scenario in Southern Europe shows that H. pylori+ve patients are put at risk of poor outcomes and points to the need of a susceptibility-based therapy according to guidelines and local microbial resistance. In the present setting (i.e. high clarithromycin resistance), despite the high observed eradication rate, sequential therapy should not be recommended (absent in guidelines, unneeded antibiotic). Bismuth-based quadruple treatment (1st, 2nd or subsequent lines) yields the highest eradication rates.Abbreviations: ALT: Altamura; BA: Bari; EGDS: esophagogastroduodenoscopy; GERD: gastro-esophageal reflux disease; H. pylori: Helicobacter pylori; ITT: intention-to-treat; PP: per-protocol; PPI: proton pump inhibitor; UBT: urea breath test.