BACKGROUND & AIMS: The initial intravenous dose of ustekinumab (UST) for treating Crohn's disease (CD) is recommended based on body weight ranges for clinical convenience. However, patients whose body weight nears the upper threshold may receive a relatively lower dose (<6 mg/kg) based on current dosage calculations. We aimed to investigate whether the body weight-range based dosing calculation method for UST may lead to suboptimal therapeutic doses and then impact effectiveness, particularly in patients with borderline weight. METHODS: A multi-center, observational, real-world cohort study was conducted in four centers. Patients with CD who received UST based on body weight-range dosing calculation were retrospectively enrolled. Participants were classified into two groups according to the initial induction dosage: the relatively higher dose (RHD) induction group (>/=6 mg/kg) and the relatively lower dose (RLD) induction group (<6 mg/kg). Steroid-free remission, clinical remission, specific objective response and remission at week 24 were compared in the two groups using propensity score weighting. UST drug concentration was measured at week 24+/-4. RESULTS: A total of 438 patients were included, with 176 patients in the RHD group and 262 patients in the RLD group. The RHD group demonstrated superior outcomes compared to the RLD group in achieving steroid-free remission (66.2 % vs. 54.9 %, P = 0.020, OR = 1.605, 95 % CI 1.082-2.395), clinical remission (66.7 % vs. 56.4 %, P = 0.032, OR = 1.546, 95 % CI 1.041-2.311) at week 24. In objective evaluation, the RHD group showed higher rates in ultrasound response (64.9 % vs. 52.1 %, P = 0.041, OR = 1.700, 95 % CI 1.027-2.844) and radiologic remission (25.1 % vs. 13.4 %, P = 0.022, OR = 2.163, 95 % CI 1.117-4.205). The drug concentration was significantly higher in the RHD group compared to the RLD group at week 24 [2.06 (1.36-3.17) microg/ml vs. 1.12 (0.25-1.52) microg/ml, P < 0.001]. Additionally, the RHD group required fewer treatment optimizations than the RLD group, but with no statistical difference (20.6 % vs. 24.9 %, P = 0.291, OR = 0.780, 95 % CI 0.488-1.231). The rate of adverse events was similar between the two groups (4.0 % vs 3.4 %, P = 0.767). CONCLUSIONS: This study suggested that the current dose calculation method may result in inadequate induction doses of UST for CD patients whose body weight is close to the upper threshold, potentially impacting the effectiveness of induction. LAY SUMMARY: A multi-center study suggests that the current body weight-range based dosing of ustekinumab for Crohn's disease may lead to insufficient induction doses for patients near the upper weight threshold, negatively impacting treatment effectiveness.