Background: Nonsteroidal anti-inflammatory drugs (NSAID) are one of the most widely used drugs in medical practice. However, all medical benefits of NSAID are paid for by increased risk of developing numerous side effects. One of the most clinically significant side effects is a NSAID-induced gastrointestinal lesion that develops in, on average, 30% of NSAID users, even with the absence of ulceration; NSAID-induced ulcers and bleeding cause 61% of deaths related to side effects of these medicines. The main aim of this study was to compare the incidence of erosive and ulcerative lesions of the gastroduodenal zone as a result of patients receiving diclofenac on the background of concomitant prophylactic use of proton pump inhibitor (PPI) omeprazole or rebamipide.Materials and Methods: To achieve this goal we have conducted a randomized comparative study, which included 118 patients aged from 25 to 65 years (mean age, 45±18 years) with osteoarthritis (94 patients) and rheumatoid arthritis (24 patients), who had taken a once-daily dose of 100 mg diclofenac (Dikloberl) over 1 month. Depending on the treatment, all patients were randomized into 3 groups by using the computer method of random numbers. Within 1 month, patients of Group 1 (n=42) received additionally a once-daily dose of 20 mg omeprazole (Omez), and patients of Group 2 (n=46) -rebamipide at a dose of 100 mg three times a day. Patients of Group 3 (n=30) received only diclofenac. The primary endpoint was the cumulative incidence of development of erosions and ulcers in the gastroduodenal zone, which was determined after the treatment according to data from the endoscopy. The secondary endpoint was the incidence of development of dyspeptic symptoms and side effects.Results: During 1 month of continuous reception of diclofenac, peptic ulcers of stomach and duodenum were found in 2/4.8% and 2/4.8% patients of Group 1 and in 3/6.5% and 2/4.3% patients of Group 2, respectively. In Group 3, peptic ulcers of stomach and duodenum were found in 5/16.6% and 3/10% patients, respectively, and in 2 cases, these ulcers (1 gastric ulcer and 1 duodenal ulcer) have manifested into gastrointestinal bleeding. Thus, all peptic ulcers of the gastroduodenal area were detected in 4/9.5% patients of Group 1, 5/10.9% patients of Group 2, and 8/26.6% patients of Group 3. (Int J Biomed. 2017; 7(1):57-59.)