Background and aims: To assess faecal calprotectin (Fcal) levels before and after therapeutic de-escalation to predict clinical relapse in patients with inflammatory bowel disease (IBD). Methods: From a prospectively-maintained database, we enrolled 160 IBD patients (112 Crohn's disease/48 ulcerative colitis) in clinical remission, with Fcal measured within 8 weeks before therapeutic de-escalation. Clinical relapse was defined using Harvey-Bradshaw index or simple clinical colitis activity index. Results: Using a ROC curve, Fcal >100 µg/g was the best threshold to predict clinical relapse after therapeutic de-escalation (AUC=0.84). In multivariate analysis, clinical remission >6 months before therapeutic de-escalation (Hazard ratio (HR)=0.57[0.33-0.99]; p=0.044) was associated with decreased risk of relapse while current steroids medication (HR=1.67[1.00-2.79]; p<0.0001) was a risk factor. Fcal >100 µg/g was predictive of clinical relapse (HR=3.96[2.47-6.35]; p<0.0001) in the whole cohort but also in patients with anti-TNF agents (n=85 patients; p<0.0001), anti-integrins (n=32; p=0.003), no biologics (n=43; p=0.049) or attempting to discontinue steroids (n=37; p=0.001). One patient (1/98) and 7 patients (7/88, 8.0%) with baseline Fcal <100 µg/g relapsed within 3 months and 6 months after therapeutic de-escalation, respectively. Seventy-Four Fcal measurements were performed in 52 patients after therapeutic de-escalation. Monitoring Fcal >200 µg/g (ROC curve with AUC=0.96) was highly predictive of clinical relapse in multivariate analysis (HR=31.8[3.5-289.4], p=0.002). Only two relapses (2/45, 4.4%) occurred within 6 months while Fcal< 200 µg/g. Conclusion: Fcal level is highly accurate to predict and monitor the risk of relapse after therapeutic de-escalation in IBD patients and could be used in daily practice.