BACKGROUND: Small bowel (SB) lesions in Crohn's disease (CD) are often asymptomatic despite being highly active. Fecal calprotectin (FC) is the most widely used biomarker of CD activity, but its drawbacks include a large intra-individual sample variability and the burden of collecting stool samples. Meanwhile, serum leucine-rich alpha-2 glycoprotein (LRG) has recently attracted attention as a biomarker that can address the limitations of FC. This study determined the diagnostic accuracy of LRG and its cut-off values for diagnosing CD activity in SB. METHODS: This was a retrospective, multi-center study of CD patients undergoing retrograde balloon-assisted endoscopy. For ileal- and ileocolonic-type patients with a colon SES-CD score of 0, we estimated the receiver operating characteristic curve of LRG and determined the cut-off value to achieve a target sensitivity level of 80%. RESULTS: Among 285 patients with SB lesions, LRG had an area under the curve (AUC) of 0.72 (95% CI 0.67-0.78) with a sensitivity of 80.2% and specificity of 47.2% for a cut-off value of 10.5 when diagnosing endoscopic remission (modified SES-CD ≤ 3), while it had an AUC of 0.72 (95% CI 0.65-0.78) with a sensitivity of 81.2% and specificity of 46.2% for a cut-off value of 10.1 when diagnosing complete ulcer healing (modified SES-CD ≤ 1). CONCLUSION: LRG was effective for diagnosing CD activity in SB, specifically with cut-off values of 10.5 and 10.1 for endoscopic remission and complete ulcer healing, respectively. A future prospective validation study will assess its clinical utility.