Abstract Background The Crohn's Disease Exclusion Diet (CDED) is a validated dietary intervention characterized by a specific highly restrictive food regime which aim to induce remission and reducing inflammation in Crohn's disease (CD). In a previously randomized control trial (RCT), clinical remission was achieved in a range of 75-85% of patients after 6 and 12-weeks of CDED. We aim to provide an additional real-world evidence-based validation. Methods Interim analysis of an open-label randomized controlled trial of CD patients with mild-to-moderate clinical activity assessed by Harvey-Bradshaw Index (HBI) was performed. Demographical characteristics and medical history were collected at enrollment, while weight, body mass index (BMI), HBI, fecal calprotectin and serum inflammatory indices were assessed at baseline and after 12 and 24 weeks. Bioelectrical impedance analysis (BIA) was performed every 12-weeks in CDED group to test the safety. The primary endpoint was clinical remission (HBI<5) and was assessed in the intention-to-treat population. Results Twenty-four patients were randomized to receive CDED diet, while 21 were in control group. No significant differences among all parameters considered were observed at baseline. Five patients in CDED group discontinued diet because of intolerance at median of 5 weeks. At week 12, the median HBI was lower in CDED patients than in control patients (3, IQR 1-5 vs 5, IQR 4-6, respectively; p=0.001) resulting in more patients achieving clinical remission (17/24, 70,8% vs 8/21, 38,1%, respectively; p=0.027). No differences in fecal calprotectin and serum inflammatory indices were observed. The administration of CDED was associated with weight loss (72 to 69 kg, p=0.003), although BIA analysis showed a decrease in fat mass (18.2% to 15.5%, p<0.0001), while fat-free mass significantly increased (81.9% to 83.7%, p=0.001). No difference in body cellular mass was observed after 12-weeks of CDED. Conclusion The CDED is effective in inducing remission in mild-to-moderate clinical activity CD patients and seems to be safe and well-accepted.