Background Helicobacter pylori infection is a substantial public health problem and plays etiological role in the pathogenesis of many gastroduodenal disorders. The addition of ecabet sodium is proven to improve the efficacy of the standard triple therapy. Our aim was to assess the efficacy and safety of ecabet sodiumcontaining quadruple therapy versus 10-day bismuth-containing quadruple therapy for H. pylori eradication. Materials and Methods We did a randomized, open-label, phase IV trial in four cities (eight sites) in China, comparing the efficacy and safety of 10-days ecabet sodiumcontaining versus bismuth-containing quadruple therapy in adults with H. pylori infection. Eligible patients were randomly assigned treatment and monitored H. pylori eradication by negative [13C]/[14C] urea breath test 28 days after the treatment as the primary outcome. Symptoms improvement and side effects were the secondary outcome. Results A total of 311 H. pylori-positive subjects were enrolled: 155 were assigned ecabet sodium quadruple therapy and 156 bismuth quadruple therapy. The eradication rates with ecabet sodiumcontaining and bismuth-containing quadruple regimens were 68.4% (106/155) and 68.0% (106/156) p = .9339 intention-to-treat (ITT) and 75.4% (104/138) and 77.0% (104/135) p = .7453 per-protocol (PP), respectively. The eradication rates for the ecabet sodium quadruple regimen differed significantly between cities (e.g., 81.2% ITT and 89.6% PP in Shanghai and 50% ITT and 53.5% PP in Xi'an). The symptom improvements and safety profiles were also similar for both treatments. Conclusions Neither 10-day Ecabet sodiumcontaining quadruple therapy or 10-day bismuth-containing quadruple therapy can be recommended as empiric therapy in cities with high antibiotic resistance rate of China.