Worldwide prevalence of Helicobacter pylori (H. pylori) infection is approximately 50%, with the highest being in developing countries. We compared cure rates and tolerability (SE) of second-line anti-H. pylori levofloxacin/amoxicillin (LA)-based triple regimens vs standard quadruple therapy (QT). An English language literature search was performed up to October 2010. A meta-analysis was performed including randomized clinical trials comparing 7- or 10-d LA with 7-d QT. In total, 10 articles and four abstracts were identified. Overall eradication rate in LA was 76.5% (95% CI: 64.4%-97.6%). When only 7-d regimens were included, cure rate was 70.6% (95% CI: 40.2%-99.1%), whereas for 10-d combinations, cure rate was significantly higher (88.7%; 95% CI: 56.1%-109.9%; P < 0.05). Main eradication rate for QT was 67.4% (95% CI: 49.7%-67.9%). The 7-d LA and QT showed comparable efficacy [odds ratio (OR): 1.09; 95% CI: 0.63-1.87], whereas the 10-d LA regimen was significantly more effective than QT (OR: 5.05; 95% CI: 2.74-9.31; P < 0.001; I(2) = 75%). No differences were reported in QT eradication rates among Asian and European studies, whereas LA regimens were more effective in European populations (78.3% vs 67.7%; P = 0.05). Incidence of SE was lower in LA therapy than QT (OR: 0.39; 95% CI: 0.18-0.85; P = 0.02). A higher rate of side effects was reported in Asian patients who received QT. Our findings support the use of 10-d LA as a simple second-line treatment for H. pylori eradication with an excellent eradication rate and tolerability. The optimal second-line alternative scheme might differ among countries depending on quinolone resistance.