Approximately 20% of patients with irritable bowel syndrome (IBS) link symptoms to food intake; a low-FODMAP diet is effective in managing these symptoms. To evaluate the effectiveness of the Mediterranean version of the low-FODMAP Diet (MED-LFD) compared to NICE guidelines for IBS and to assess changes in stool volatile compound levels. 108 patients with Rome IV IBS without constipation were randomized into the MED-LFD or NICE group. Primary endpoints included changes in symptom severity and responder rate (reduction of >50 IBS-SSS points) after intervention and at 6 months. Secondary endpoints assessed quality of life, symptom burden, adequate relief, anxiety/depression levels, and adherence. Volatile compound levels were measured using Gas Chromatography/Mass Spectrometry. At both time points, the MED-LFD group showed a significantly greater improvement in symptom severity (159 ± 80 vs. 253 ± 94 and 168 ± 117 vs. 245 ± 98), responder rates (84.6% vs. 60.8% and 79.1% vs. 52.3%), and adherence (75% vs. 41% and 45% vs. 7%). Similar results were observed for all secondary endpoints, with no serious adverse events reported. The MED-LFD intervention was the strongest independent predictor of being a responder at the first (OR = 6.66; 95%CI = 1.46, 30.4) and second follow-up (OR = 4.85; 95%CI = 1.31, 17.96). Short and branched-chain fatty acids were significantly reduced at both follow-ups. The MED-LFD is superior to NICE recommendations in managing non-constipated IBS symptoms and quality of life. It remains to be proven that reduced volatile compound levels might be an objective marker of response to dietary interventions. ClinicalTrials.gov ID: NCT03997708.