Italy's shift to a tertiary economy has modified the working market, concentrating demand also on unqualified one, which includes most immigrants. It is also well established that low socio-economical conditions are associated with an increased prevalence of H. pylori infection. The aims of this study were to compare: (1) the efficacy of a 7 days triple therapy in immigrant and in Italian patients; (2) the prevalence of PUD between these two groups of patients. A total of 116 consecutive immigrant and 112 Italian H. pylori infected patients were recruited between 2007 and 2008. Patients underwent (13)C-UBT, endoscopy with biopsies, and were offered a 7-day triple therapy. Eradication rate (ER) was assessed 8 weeks after the end of the treatment using (13)C-UBT. The two populations differed for median age (p < 0.01), prevalence of PUD (p < 0.01), and smoking status (p < 0.01). The ER according to the ITT analysis was 70% for Italian and 48.3% for immigrant (p < 0.01). Multivariate analysis including country of origin, sex, age, PUD, smoking, and alcohol status found that immigrant had an adjusted OR for not eradicating of 2.14 (p = 0.03). In immigrant patients resident in Italy, performance of triple therapy was lower than expected. Further studies are demanded to confirm and clarify these intriguing results.