ResultsOverall, 54 studies were included (6,705 patients in the susceptibility-guided group and 7,895 in the empirical group). H. pylori eradication rate was 86 vs. 76%, respectively (RR: 1.12; 95% CI: 1.08–1.17; I2: 83%). Similar results were found when only RCTs were evaluated (24 studies; RR: 1.16; 95% CI: 1.11–1.22; I2: 71%) and when susceptibility testing was assessed by culture (RR: 1.12; 95% CI: 1.06–1.18) or PCR (RR: 1.14; 95% CI: 1.05–1.23). For first-line treatments (naïve patients; 30 studies), better efficacy results were obtained with the susceptibility-guided strategy (RR: 1.15; 95% CI: 1.11–1.20; I2: 79%). However, for empirical first-line quadruple regimens, in particular (both with and without bismuth, excluding the suboptimal triple therapies), not based on CYP2C19 gene polymorphism, no differences in efficacy were found compared with the susceptibility-guided group (RR: 1.04; 95% CI: 0.99–1.09); this lack of difference was confirmed in RCTs (RR: 1.05; 95% CI: 0.99–1.12). For rescue therapies (13 studies, most 2nd-line), similar results were demonstrated for both strategies, including all studies (RR: 1.09; 95% CI: 0.97–1.22; I2: 82%) and when only RCTs were considered (RR: 1.15; 95% CI: 0.97–1.36).