Background: Eosinophil-derived neurotoxin (EDN) is an important biomarker of eosinophilic inflammation. Methods: This study evaluated Montelukast treatment response according to EDN concentration in children with perennial allergic rhinitis (PAR). Fifty-two children with PAR were recruited and took a combination of Montelukast (5mg) and Levocetirizine (5mg) "Mont/Levo Group" or only Montelukast (5mg) "Mont Group" for 4 weeks. All caregivers were instructed to record rhinitis symptoms for 4 weeks. EDN was measured before and after treatment. Results: Daytime nasal symptom scores (DNSS) significantly decreased in both the Mont/Levo (p = 0.0001; n = 20) and Mont Group (p < 0.0001; n = 20), but there were no significant differences between the two groups. EDN concentration also significantly decreased after treatment in both groups (p < 0.0001 and p < 0.001, respectively). For secondary analysis, children with a high initial EDN concentration (EDN >= 53 ng/mL) were placed in the "High EDN Group", while those with a lower initial EDN concentration (EDN < 53 ng/mL) were put in the "Low EDN Group". Both groups experienced significant reductions in DNSS after either treatment regimen (p < 0.0001 and p = 0.0027, respectively) but the High EDN Group had greater reductions. EDN concentrations in the High EDN Group decreased significantly from either treatment (p < 0.0001). Conclusion: We found that children with AR and a high serum EDN concentration may respond well to Montelukast treatment. A therapeutic strategy using EDN concentrations in patients with AR to evaluate therapeutic response may help improve quality of care.