Background Patients with obesity are frequently excluded from Helicobacter pylori (H pylori) therapy trials, despite physiological alterations that may impair antibiotic pharmacokinetics. Suboptimal eradication rates have been reported in patients with obesity undergoing bariatric surgery when standard fixed-dose regimens are used.Objective To evaluate the effectiveness and safety of an optimized amoxicillin regimen for improving H pylori eradication rates in patients with obesity scheduled for bariatric surgeryMethods This multicenter retrospective cohort study included adult candidates for bariatric surgery with histologically confirmed H pylori infection. Patients received either standard fixed-dose quadruple concomitant therapy or an optimized regimen in which amoxicillin was administered at 50 mg/kg/day based on adjusted body weight (AjBW), with a maximum dose of 6 g/day. Eradication was assessed using a 13C-urea breath test performed 6–8 weeks after treatment completion. Adverse events and treatment adherence were systematically recorded.Results A total of 177 patients were analyzed: 129 received fixed-dose therapy and 48 received optimized amoxicillin dosing. Eradication was achieved in 89.6% of patients in the optimized group compared with 68.2% in the fixed-dose group (p < 0.05). Optimized dosing was associated with a fourfold increase in the odds of eradication (OR 4.0; 95% CI 1.36–11.73). The safety profile was favorable, with predominantly mild adverse events and no significant differences between groups.Conclusions Optimized amoxicillin dosing significantly improves H pylori eradication rates in patients with obesity undergoing bariatric surgery without compromising safety. These findings question the adequacy of fixed-dose regimens in this population and support individualized antimicrobial strategies to optimize preoperative eradication.