KL-6 is a high molecular weight glycoprotein that is expressed on the apical borders of normal secretary alveolar epithelial cells. The aim of our study was to elucidate the potential role of circulating levels of KL-6, related to C-reacting protein (CRP), disease severity (PRISM, TISS), length of stay (LOS) or mechanical ventilation (LOMV), and outcome, in children with acute respiratory distress syndrome (ARDS), sepsis, or traumatic brain injury (TBI). KL-6 concentrations were monitored using solid phase sandwich enzyme-linked immunosorbent assay in plasma of nine patients with ARDS and compared to nine patients with TBI, nine with sepsis, and nine ventilated patients with cancer of matched illness severity on days 1, 3, 5, 7, and 10. Initial respiratory/ventilatory parameters (oxygenation index, plateau pressures) were recorded for ARDS patients. Patients with ARDS had higher early plasma levels of KL-6 (956 ± 400 U/ml), as compared to patients with TBI (169± 9 U/ml), sepsis (282±81 U/ml), and ventilated controls (255 ± 40 U/ml). Significant correlations were demonstrated between plasma KL-6 concentration and oxygenation index, PaO2: FiO2 ratio, LOS and LOMV, but not with CRP or PRISM. Only in patients with ARDS, plasma KL-6 levels were higher in non-survivors than survivors (P <0.03). Plasma KL-6 levels have possible prognostic significance and may provide a useful marker for ARDS in critically ill children.