Abstract Background This study aimed to define clusters of disease activity and prognostic factors of disease course in a well-characterized cohort of children with Crohn’s disease (CD). Methods All patients from the SIGENP IBD (Italian Society of Pediatric Gastroenterology Hepatology and Nutrition Inflammatory Bowel Disease) registry with a 5-year follow-up and 6-monthly evaluation were included. Active disease was defined for each semester as follows: clinical activity (weighted Pediatric Crohn’s Disease Activity Index ≥12.5 or Mucosal Inflammation Noninvasive Index ≥8) and active disease on endoscopy (Simple Endoscopic Score for Crohn’s Disease >3 or fecal calprotectin >250 µg/g) or imaging. Formula-based clusters were generated based on previously published patterns in adults. Results Data from 332 patients were analyzed. A total of 105 (32%) experienced a quiescent disease course; 49 (15%) and 31 (9%) a moderate-to-severe chronically active and chronic intermittent disease, respectively; 104 (31%) and 43 (13%) had active disease in the first 2 years after diagnosis and remission thereafter and vice versa, respectively. Surgery at diagnosis was significantly associated with a quiescent course (odds ratio OR, 10.05; 95% confidence interval CI, 3.05-25.22; P=.0005), while growth impairment at the diagnosis and active disease requiring corticosteroids at 6 months were inversely related to the quiescent group (OR, 0.48; 95% CI, 0.27-0.81; P= .007; and OR, 0.35; 95% CI, 0.16-0.71; P= .005, respectively). Perianal involvement at diagnosis and moderate–severe activity at 6 months correlated with disease progression (OR, 3.85; 95% CI, 1.20-12.85; P=.02). Conclusions During the first 5 years of follow-up, one-third of children with CD experience a quiescent course. However, another one-third have a moderate-to-severe disease course. Surgery at the diagnosis is related to a quiescent course, while growth impairment and lack of response to induction therapy correlate with more severe disease activity during follow-up.