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Background: Irritable Bowel Syndrome (IBS) is a widespread disease with variable symptoms that have an important impact on the quality of life. Despite the prevalence of IBS, its etiology and pathophysiology are still to be fully understood, but immune response is known to be involved. In this study, we investigated the variation of two specific cytokines, B-cell activating factor (BAFF) and platelet-activating factor (PAF), the levels of food-specific IgG and the symptom severity, using Irritable Bowel Syndrome-Symptom Severity Score (IBS-SSS), following a personalized and unrestricted-calorie diet., Methods: We enrolled 30 subjects with diagnosis of IBS, according to Rome-IV criteria, whose inflammatory markers were measured at baseline and after 6 weeks of dietary intervention. The subjects were monitored in a general practice outpatient setting and nutritional advice was offered remotely via two telephone sessions with a nutritionist., Results: BAFF and PAF values did not differ between baseline and end of study, both in compliant (C) and non-compliant (NC) subjects. IgG levels significantly decreased only in compliant subjects: 37.32 (23.24-93.67) IU/mL; 27.9 (7.56-93.96) IU/mL (p = 0.02) and in non-compliant went from 51.83 (13.17-113.1) IU/mL to 44.06 (4.96-255.4) IU/mL (p = 0.97, ns). IBS-SSS significantly decreased in both compliant subjects, from 245 (110-480) to 110 (0-140) (p < 0.0001), and non compliant subjects, from 250 (155-370) to 100 (7-220) (p < 0.0001). Comparing IBS-SSS between week 3 and week 6, only compliant subjects had a significant reduction, from 155 (50-355) to 110 (0-140) (p = 0.005), versus non-compliant, from 115 (35-315) to 100 (7-220) (p = 0.33, ns)., Conclusion: These findings support the rapid efficacy and suitability of a personalized dietetic intervention with outside consultation in IBS., Trial Registration: ClinicalTrials.gov ID NCT04348760 Registered April 15, 2020 (retrospectively registered) https://clinicaltrials.gov/show/NCT04348760.