Background. The current approach to the treatment of H. pylori infection is based on the data of local resistance to antibiotics. For regions with high clarithromycin resistance, quadruple non-bismuth therapy, such as concomitant therapy, may be the first choice of therapy. Apart from concomitant, other models of quadruple therapy are also used, such as hybrid therapy. A smaller number of antibiotics in the hybrid regime may be beneficial. However, studies comparing concomitant and hybrid therapy in the region of high clarithromycin resistance are scarce. Aim. The primary objective of the study was to compare concomitant and hybrid therapy in the first line of eradication treatment in the region of high clarithromycin resistance, where the appropriate eradication scheme has not yet been established. Secondary aims of the study were to determine and to compare compliance and adverse events. Also, the aim of the study was to compare the quality of life of patients with H. pylori infection before and after eradication therapy using a specific questionnaire for gastrointestinal symptoms (Gastrointestinal Symptom Rating Scale, GSRS). Methods. In an open-label, randomised clinical trial 140 patients total with H. pylori infection were randomly assigned to either concomitant (esomeprazole 40 mg, amoxicillin 1 g, metronidazole 500 mg, clarithromycin 500 mg, twice daily for 14 days) or hybrid (esomeprazole 40 mg and amoxicillin 1 g twice daily during 14 days with adding metronidazole 500 mg and clarithromycin 500 mg twice daily, in the last 7 days) treatment group. One month after the end of therapy, a stool antigen test was performed to determine the outcome of therapy. Also, patients were assessed regarding compliance and adverse events. All patients were given GSRS questionnaire before and after therapy. Results. Eradication rates in the concomitant and hybrid treatment groups were 84.1% (58/69) and 83.1% (59/71) in intention-to-treat analysis and 96.7% (58/60) and 95.2% (59/62) in per-protocol analysis. There was no significant difference between the concomitant and hybrid group: P = 0.878 in the ITT analysis and P = 0.675 in the PP analysis. Adverse events were significantly more frequent in the concomitant group (33.3% vs 18.3%, P = 0.043). In both groups, nausea was the most common adverse event. There was no significant difference between groups regarding compliance. In both groups, the total GSRS score improved significantly after therapy (concomitant group: median 23 (IQR 18-28) vs. median 19 (15.75–24), P < 0.001; hybrid group: median 28 (IQR 20-39.5) vs. 22 (IQR 18-31), P < 0.001). In the concomitant group, the abdominal pain score, reflux symptoms score and indigestion score decreased significantly after therapy. In the group with hybrid therapy, all five groups of symptoms (abdominal pain, reflux symptoms, indigestion, diarrhea and constipation) significantly decreased after therapy. Patients with adverse events had significantly higher total GSRS scores after eradication therapy (median 22 (IQR 18-31) vs. median 19.5 (IQR 16-25); P = 0.041). Conclusion. Hybrid therapy has similar eradication rate as concomitant therapy, with lower adverse events rate. Both concomitant and hybrid eradication therapy regimes could alleviate gastrointestinal symptoms regardless of the treatment used, but the favourable effect seemed to be more pronounced after hybrid therapy. In the era of increasing antibiotic resistance, eradication regime with less antibiotic’s usage, as hybrid therapy, should be reasonable first line treatment choice for H. pylori infection.