It was aimed to evaluate the correlation between serum KL-6 levels with both presence of interstitial lung disease (ILD) and its severity in connective tissue diseased children, directing to early detection and better management of interstitial lung disease in CTD children. This study included 40 CTD patients divided into with and without ILD as evaluated mainly by high-resolution computed tomography (HRCT), and spirometric pulmonary function test as well as 20 normal controls to detect the expression level of KL-6 by ELISA. KL-6 levels were compared among the different study groups. In comparison of all groups of the study, KL-6 levels were related positively with both presence and severity of ILD at a cut-off of 63.4 U/ml, with sensitivity of 95.2%, specificity of 89.7%, positive predictive value of 83.26% and negative predictive value of 97.2% for ILD in CTD patients. Moreover, there is a significant inverse correlation found between serum KL-6 levels and parameter of spirometry. In conclusion, Serum KL-6 offers high sensitivity and specificity for the diagnosis of ILD in CTD children and is inversely correlated with pulmonary function deterioration. Accordingly, serum KL-6 may represent a promising biomarker for prediction and monitoring of ILD severity.