BACKGROUND: The significant prevalence of dyspepsia in patients without Нelicobacter pylori infection, difficulties in differential diagnosis necessitate the identification of the most common nosological variants, optimization of the diagnosis algorithm. AIM: To study clinical, laboratory and instrumental characteristics of patients with dyspepsia syndrome unrelated to Нelicobacter pylori infection. MATERIALS AND METHODS: A 13C-Urea Breath test was performed to 856 patients with uninvestigated dyspepsia. According to its results, 342 patients with Нelicobacter pylori infection were excluded from the study. The remaining patients (n = 514) with negative Нelicobacter pylori status underwent esophagogastroduodenoscopy and ultrasound examination of the abdominal organs. The patients with an identified organic pathology (n = 129) explaining dyspeptic complaints were excluded from the study. 208 out of the 385 patients without organic pathology agreed to undergo laboratory and instrumental examination in accordance with the study protocol. To assess dyspeptic complaints, 208 patients filled out a “Dyspepsia Questionnaire” developed by the authors. Demographic, anthropometric data, and complaints were recorded in all the study participants; experimental psychological testing was performed (Beck’s questionnaires, generalized anxiety disorder questionnaire-7, Short Form-36) and laboratory and instrumental examination (the level of pepsinogen I, pepsinogen II, immunoglobulin class G to Нelicobacter pylori and gastrin-17 in serum), esophagogastrogastroduodenoscopy with biopsy and pathomorphological assessment according to the Operative Link for Gastritis Assessment (OLGA) system, 24-hour esophageal impedance–pH monitoring, radiography of the esophagus and stomach. RESULTS: The majority of the patients with dyspepsia syndrome were not infected at the time of Нelicobacter pylori complaints — 514 (60.1%) patients. An in-depth examination of 208 people with a negative helicobacter status and the absence of an organic pathology explaining the symptoms revealed the heterogeneity of the final diagnoses. The results of the study demonstrate positive correlations between the level of depression, anxiety and the AET (acid exposure time) index, the number of acid reflux. A decrease in the level of pepsinogen I, gastrin-17, and the ratio of pepsinogen I/II was revealed with an increase in the degree and stage of atrophy according to the results of an Operative Link for Gastritis Assessment biopsy. CONCLUSIONS: The revealed variability of diagnoses and comorbidity in patients with similar complaints deepens the understanding of dyspepsia syndrome and explains the possible ineffectiveness of standard therapy regimens.