Paneth cell metaplasia of the rectal epithelium is a common histologic finding in patients with chronic inflammatory bowel disease. However, the clinical significance of isolated Paneth cells in otherwise unremarkable rectal mucosa has not been extensively examined. This study examined the frequency and clinical correlates of rectal Paneth cells in 245 biopsies obtained from patients between the ages of 2 weeks to 20 years in a pediatric tertiary care facility from 2010 to 2011. The specimens comprised 193 endoscopic pinch biopsies and 52 rectal suction biopsies. All 245 cases were endoscopically and histologically unremarkable with no prominence of eosinophils, no altered mucosal architecture, and no inflammation. Paneth cells were present in 42 cases (17.1%), which is higher than previous reports. Only 1 of 42 patients with rectal Paneth cells was subsequently diagnosed with Crohn disease. In our study population, the finding of Paneth cells was associated with young age, and the incidence of Paneth cell cases decreased with increasing age (χ=13.69, P=0.0002). Constipation was the most common presenting symptom in patients with rectal Paneth cells and was highly associated with the presence of Paneth cells (odds ratio 4.5, 95% confidence interval: 2.2-9.0). Paneth cells in otherwise unremarkable pediatric rectal biopsies are not rare and frequently occur in common conditions such as idiopathic constipation.