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Introduction: Helicobacter pylori (H. pylori) are microaerophilic gram negative, spiral shaped, flagellated bacterial pathogens transmissible to humans. The prevalence of infection with H. pylori infection varies worldwide. Pharmacologic therapy for eradication must be initiated in symptomatic individuals with emphasis on hygiene and sanitation. The high prevalence of H. pylori infection in the country, and the lack of adequate evidence on the efficacy of the standard triple therapy in Southern India was the drive to conduct this study. Aim: To compare and evaluate the efficacy of 14 days clarithromycin based triple drug therapy over 10 days levofloxacin based triple drug therapy in H. pylori eradication. Materials and Methods: A randomised clinical study was conducted from September 2018 to February 2019, at a tertiary care teaching hospital and research centre in suburban Chennai, Southern India. Eighty patients with dyspepsia, who were diagnosed with H. pylori infection based on both Rapid Urease Test (RUT) and histopathology of antral biopsy, were alternately assigned to treatment with either 14 days clarithromycin based triple drug regimen (PAC) or 10 days levofloxacin based triple drug regimen (PAL). Efficacy of the drugs were compared using both RUT and histopathology of endoscopic antral biopsy specimen four weeks after completion of the treatment. Chi-square test was used for data analysis. Results: Out of the 80 enrolled patients, 70 individuals completed the study, of which 41 were males and 29 were females. Baseline characteristics were similar in the both the groups-mean age 42.31±14.8 years in PAC and 42.20±12.67 years in PAL (p=0.150); 65.7% were males and 34.3% were females in PAC group, 51.4% were males and 48.6% were females in PAL group (p=0.225). Clearance of infection was seen in 23 patients (65.7%) in PAL group as compared to 32 patients (91.4%) in the PAC (p=0.01). Among patients with failure of eradication, 3 (1.05%) from PAC group and 12 (4.20%) from PAL group had persistence of dyspeptic symptoms. In addition, 7.14% (5 out of 70-two from PAC and three from PAL group) of subjects who had H. pylori eradication had persistence of same symptoms of dyspepsia on follow-up at four weeks after completion of the regimen. Conclusion: A 14 days clarithromycin based triple drug regimen is more effective than 10 days levofloxacin based triple drug regime for the eradication of H. pylori infection.