BACKGROUND AND STUDY AIMS: The aim of this study was to evaluate the efficacy of probiotic as an adjuvant in quadruple therapy for H. pylori eradication compared with placebo. PATIENTS AND METHODS: This randomized, double-blind, controlled trial was conducted on 450 patients with confirmed H. pylori infection. We randomly allocated patients (1:1) to receive probiotic (Lactobacillus ruteri, 100 mg) or placebo as an adjuvant in quadruple therapy with bismuth subcitrate 240 mg, pantoprazole 40 mg, amoxicillin 1000 mg and clarithromycin 500 mg all twice daily for 14 days. The primary outcome of the study was the H. pylori eradication rate at eight weeks after the end of treatment using C-urea breath test. The secondary endpoint of study was patient-reported side effects of drugs. The study protocol was approved by the Iranian Registry of Clinical Trials (IRCT20080901001155N32). RESULTS: H. pylori eradication rates were higher in the probiotic group, compared to placebo, but this difference was not statistically significant, according to both intention-to-treat (78.7 % (95 % CI; 71.24-86.16) versus 72 % (95 % CI; 64.9-79.1), respectively) and per-protocol (80.1 % (95 % CI; 73.7 - 86.5) versus 75.2 %(95 % CI; 68.4 - 82), respectively). About 69.7 % of patients in the probiotic group experience side effects compared to 98.6 % in the placebo group that was statistically significant (P-value < 0.001). Headache and all gastrointestinal adverse events except constipation were significantly lower in the probiotic group compared to placebo (P-value < 0.001). CONCLUSION: Adding Lactobacillus ruteri to quadruple therapy did not significantly improve the eradication of H. pylori. However it reduced the frequency of drug-associated side effects.