Background: Asthma is one of the most popular chronic diseases in children. It is defined as a complicated inflammatory disorder in which the patient suffers from chronic and persistent inflammation of the airways. The sialylated glycoprotein Krebs von den Lungen-6 (KL-6), one of the lung epithelium-specific proteins, has been recognized as a significant biomarker which directly associates with interstitial lung disease (ILD) pathogenesis, indicating the extent of damage and regeneration of type II pneumocytes. Objective: the aim of this study is to investigate the degree of alveolar damage in asthmatic children with acute exacerbation as reflected by serum KL-6 levels. Methods: This cross-sectional controlled study included 50 patients with acute asthma exacerbation diagnosed as per the GINA guidelines definition and 50 age- and sex-matched healthy children as controls. Spirometry was done for all participants. Serum KL-6 level was estimated by Enzyme Linked Immunosorbent Assay (ELISA), and total serum IgE level was measured via the electrochemiluminescence technology. Results: The asthma patients included 35 (70%) males and 15 (30%) females with mean age of 10.76 ±1.9 years. Forty-seven patients (94%) had a positive family history of bronchial asthma and 32 (64%) had other atopic manifestations The mean serum KL-6 level in patients was more than double the mean level of the control group (115.79 vs 55.64). No significant relation was observed between KL-6 serum level and age, family history of asthma, seasonal variation, or atopic manifestation among the cases. Serum total IgE levels were significantly higher in cases compared to controls (P<0.05). Conclusion: Serum KL-6 levels in pediatric asthma patients may be a useful diagnostic tool for detecting and monitoring the severity of airway inflammation. The use of serum KL-6 alone may help to differentiate between asthmatic patients in exacerbation and healthy controls.