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Background Ustekinumab (UTK) is a human immunoglobulin (Ig) G1 kappa monoclonal antibody approved in 2017 for the treatment of Crohn’s Disease (CD). Up until now, there has not been enough evidence of the relationship between ustekinumab trough levels (UTL) and the clinical evolution and biological markers of the disease. Our study aimed to investigate the relationship between UTL and different biomarkers in a real-world setting. Methods We performed a retrospective observational study including patients up to 18 years with CD receiving subcutaneous maintenance regimen of 90 mg UTK every 8 weeks and available UTL. Biochemical response and remission were evaluated with faecal calprotectin (FC) and C-Reactive Protein (CRP) levels. The biochemical response was defined as a decrease of 50% or more of FC and/or CRP baseline levels, and biochemical remission as FC level <150µg/ml and/or PCR<0.4 mg/dl. UTL was determined from serum samples collected prior to the injection using a commercially available validated enzyme-linked immunosorbent assay (ELISA). Continuous variables were tested using the Mann–Whitney U-test. Receiver operating characteristic (ROC) curves were used to estimate the cut-off of the UTK trough level; for scoring purposes, we chose a cut-off that would maximise the sum of sensitivity and specificity. A value of p < 0.05 was considered statistically significant. Statistical analysis was performed using SPSS for Windows. Results Forty-two patients were included (27 men and 15 female), with an average age of 47.7 years. The average FC levels were 1358,5μg/ml at the beginning of the treatment. In the maintenance period, we observed a biochemical response in 69% of patients, whose UTL were significantly higher than in non-responders (2.25 µg/ml [IQR: 3.08] vs. 0..65 µg/ml [IQR: 1.95]. respectively; p = 0.037). Likewise. 38% of patients achieved biochemical remission (responders 2.125 µg/ml [IQR: 2.25] vs. non-responders 1.5 µg/ml [IQR: 3.26]; p = 0.476). The AUC for predicting biochemical response by means of UTL was 0.703 [CI 95%: 0.529–0.877] (p = 0.037), with sensitivity of 51%, specificity of 76% and a cut-off of 2.20 μg/ml. Conclusion There is limited data on the association between UTL and patient outcome. Our study demonstrates the association between improvement of different biomarkers and higher levels of UTL, with a significant statistic result for biochemical response and non-significant statistic result for biochemical remission, maybe due to a small sample, but with a positive trend. Further studies are necessary in order to conclude that UTL is significant in the management and evolution of the disease and to determinate the optimal cut-off.