BACKGROUND Serum Krebs von den Lungen-6 (sKL-6) is an high-molecular-weight (200 kDa) glycoprotein predominantly expressed by damaged alveolar type II cells, and it has been proposed as a potential biomarker of different ILD. This is a prognostic biomarker for chronic hypersensitivity pneumonitis (cHP) and idiopathic pulmonary fibrosis (IPF), two diseases that share several clinical and radiological features. Little data are available on the potential role of KL-6 in granulomatous and cystic interstitial lung diseases, including the orphan disease known as pulmonary Langerhans cell histiocytosis (PLCH). METHODS For the first time, sKL-6 concentrations were assayed and compared in 96 patients (17 PLCH, 22 IPF, 34 cHP) and 22 healthy controls. RESULTS Serum KL-6 concentrations were significantly higher in PLCH (599 ± 594 U/mL), IPF (1645 ± 846 U/mL) and cHP patients (1691 ± 1643 U/mL) than in healthy controls (268 U/mL) (P = .037). Area-under-the-curve values of sKL-6 were 73.4% between PLCH and healthy controls, 84.5% between IPF and PLCH and 78% between cHP and PLCH. An indirect correlation between sKL-6 concentrations and peripheral CD1a-positive cells was demonstrated (r = -0.82; P = .034). CONCLUSIONS Serum KL-6 concentrations were higher in PLCH patients than in controls, reflecting the alveolar damage typical of this rare interstitial lung disease.