This study aimed at exploring the link among individual concentrations, pharmacokinetic parameters, and the probability of relapse after de-escalation in a real-world prospective cohort of patients with inflammatory bowel disease (IBD) who underwent infliximab treatment de-escalation. Ninety-one patients were included. A time-varying compartment model was used to estimate individual pharmacokinetic parameters and trough concentrations. A Cox model was implemented to explore the parameters influencing the probability of relapse after de-escalation. Volume, clearance, and trough before and after de-escalation were linked to the relapse risk at the univariate step. Independent predictors of relapse were tobacco use and/or ulcerative colitis (P = 0.0093), a higher C-reactive protein (CRP; P = 0.00064), and an infliximab trough < 2.4 μg/mL after de-escalation (P = 0.0001). Patients with trough > 5.7 μg/mL are eligible to de-escalation, but infliximab pharmacokinetics is highly variable in time. Therefore, drug monitoring is mandatory after de-escalation to maintain trough > 2.4 μg/mL. Clearance monitoring seems an appealing approach for patient selection and relapse prediction.