<p>Inflammatory bowel disease (IBD) disrupts the intestinal tight junction structure, in which claudins are key components. Most previous studies have assessed claudin expression in intestinal tissue and predominantly in adults. We evaluated serum claudin-2, claudin-3, and claudin-4 levels in 44 children with IBD (22 ulcerative colitis and 22 Crohn’s disease) and 22 healthy controls, group-matched for age and gender. Serum claudin levels were measured by ELISA, and their relationship with inflammatory markers and validated disease-activity indices was assessed. Serum claudin-2 levels were significantly higher in children with IBD than in controls (<i>p</i> = 0.036) and discriminated patients from controls with an area under the curve of 0.660 (95% CI 0.524–0.795; cut-off 20.90 ng/mL, sensitivity 59.1%, specificity 63.6%). Serum claudin-2 correlated positively with C-reactive protein and erythrocyte sedimentation rate, and serum claudin-4 correlated with the Pediatric Crohn’s Disease Activity Index, Pediatric Ulcerative Colitis Activity Index, and several inflammatory markers. Serum claudin-3 levels did not differ between groups, and none of the claudins differed by disease activity. These findings suggest that serum claudins, particularly claudin-2, may have potential as noninvasive, disease-associated markers in pediatric IBD, although larger, multicenter studies are needed for confirmation.</p>