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Interstitial lung diseases (ILD) are a heterogeneous group of illnesses of known and unknown aetiology. Differential diagnosis among the three disorders is often challenging. Specific biomarkers with good sensitivity and specificity are therefore needed to predict clinical outcome and guide clinical decisions. The aim of this study was to investigate inflammatory/fibrotic biomarkers, to determine whether single mediators or panels of mediators could be useful to stratify patients into three distinct domains: sarcoidosis, idiopathic pulmonary fibrosis (IPF) and chronic hypersensitivity pneumonitis (cHP). A total of 163 ILD patients monitored at Siena Referral Centre for Sarcoidosis and other Interstitial Lung Diseases were enrolled in the study. Clinical data, pulmonary function tests and biochemical analytes were retrospectively collected. SAA levels were detected by ELISA kit and Krebs von den Lungen 6 (KL-6) were measured by CLEIA method, for sarcoidosis, cHP and IPF patients. Multiple comparison analysis showed significant differences in C reactive protein (CRP), white blood cell count (WBC) and creatinine levels between the three groups. In the logistic regression model, KL-6, CRP and WBC showed areas under curves (AUC) 0.86, for sarcoidosis diagnosis. The logistic regression model KL-6 and SAA showed the best performance with an AUC 0.81 for discriminating IPF than cHP and sarcoidosis. For differential diagnosis of IPF and cHP, KL-6 and SAA were considered in the logistic regression model, showed an AUC 0.79. The combination of serum biomarkers proposed here offers insights into the pathobiology of ILDs. These panels of bioindicators will improve diagnostic accuracy and will be useful in the clinical management of ILDs.