Introduction: Irritable bowel syndrome is a chronic gastrointestinal disorder characterized by symptoms including abdominal pain or discomfort associated with changes in bowel movements (diarrhea or constipation). The association between gluten exposure and the onset of symptoms of irritable bowel syndrome is complex and not well understood. However, some patients experience the benefits of a gluten-free diet based on personal advice or decision. Studies have shown that patients with IBS with predominant diarrhea who do not have celiac disease experience an improvement in symptoms on a gluten-free diet. Therefore, this study aimed to evaluate the effect of a gluten-free diet on clinical gastrointestinal symptoms of non-celiac patients with diarrhea-predominant irritable bowel syndrome (IBS-D). Material and Methods: This study was performed as a clinical trial on 100 patients with irritable bowel syndrome with predominant diarrhea. Patients were divided into two groups, and in the case group, the gluten-free diet and the control group continued the regular diet. For all patients at the initial visit after IBS diagnosis, the initial symptoms of the disease and the standard IBS severity questionnaire were completed, and then the symptoms and severity of the disease were evaluated weekly for four weeks. Results: The mean severity of IBS symptoms at the beginning of the intervention in control and GFD groups was 28 and 29.09, respectively (p-value <0.05). The present study results showed that there was no significant difference between the two groups in none of the evaluated times (first to the fourth week). However, the severity of symptoms decreased over time in both groups, but the results showed no difference in duration of symptom severity between the two groups, and in both groups, the severity of symptoms decreased equally during the study period. In the final week of treatment, the symptoms of abdominal pain, especially abdominal distension, were slightly better in the GFD group than in the control group and instead had a slightly greater effect on daily activities. Conclusion: The results of the present study showed that a gluten-free diet did not affect reducing the symptoms of patients with diarrhea-predominant irritable bowel syndrome, although more studies are recommended due to the limited studies