Aim. To determine the efficacy and safety of Kolofort in the treatment of patients with irritable bowel syndrome (IBS). Subjects and methods. 52 patients (16 men and 36 women) aged 26 to 59 years were examined over 4 months to rule out organic disease. The diagnosis of IBS was established on the basis of the Rome III diagnostic criteria (2006). Seven patients were diagnosed as having IBS with a preponderance of constipation; 3 had IBS with a preponderance of diarrhea, and 42 had mixed IBS. Thereafter they were given Kolofort, a combination release-active antibody drug having anxiolytic, anti-inflammatory, and spasmolytic effects. Kolofort affects the ligand-receptor interactions of the brain-specific protein S-100 with serotonin receptors and σ1-receptors in the central nervous system and that of histamine with histamine H4 receptors in the gastrointestinal tract and modifies (regulates) the functional activity of tumor necrosis factor-α (TNF-α). The regulatory action of the drug at the level of the central and autonomic nervous system and the immune system manifests itself as spasmolytic, anti-inflammatory, and sedative effects, which as a whole effectively normalizes gastrointestinal motility. For 3 months, the patients took sublingual Kolofort in a dose of 2 tablets thrice daily for 2 weeks, then 2 tablets twice daily for 2.5 months. Control was made 2 weeks, 1, 2, and 3 months after treatment initiation. The investigators assessed abdominal pain syndrome, defecation disorders, abdominal distension, and flatulence by the visual analogue scale (VAS-IBS questionnaire), visceral sensitivity index (VSI questionnaire), quality of life (QL) in patients with IBS (IBS-QoL questionnaire), and stool form according to the Bristol Stool Chart and measured the levels of TNF-α and interleukin (IL)-1β and IL-10 before and after treatment. Results. The efficacy of Kolofort showed itself within 2 weeks of its administration against all the study functional parameters (pain, defecation disorder, and flatulence). After one month of therapy, the efficacy of Kolofort achieved meaningful statistical significance against abdominal pain, complaints of flatulence, visceral sensitivity index, and QL. The statistically significant restoration of a stool form was achieved 2 months after treatment and 3-month Kolofort treatment showed a clear-cut positive clinical effect that appeared as reductions in pain syndrome (214±0.22; р < 0.001) and visceral hypersensitivity symptoms (from 30.33±2.9 to 67.76±6.5; р < 0.001), improvements in subjective sensations associated with defecation disorders (from 6.95±0.71 to 2.74±0.28; р < 0.001), stool form, and QL indicators (from 103.48±9.06 to 44.95±5.4; р < 0.001), and a decrease in blood TNF-α levels after treatment termination (from 9.16 to 7.02 pg/ml; р < 0.026). A Kolofort treatment cycle for IBS produced no clinically relevant side effects. Conclusion. Kolofort was highly effective in relieving symptoms, in normalizing the psychological status, and in lowering the levels of TNF-α in the treatment of IBS. The efficacy of the drug was achieved because of its combined effect on the main components of the pathogenesis of IBS.