Background: Oxidant-induced tissue damage is thought to contribute to the lung injury seen in patients with acute respiratory distress syndrome (ARDS). Ceruloplasmin (CP) is a major circulating antioxidant, increased levels of which have been measured in bronchoalveolar lavage fluid (BALF) taken from such patients. Traditionally, CP detected in these circumstances was thought to be plasma-derived, moving into the alveolar spaces as a consequence of the increased alveolar-capillary permeability that characterises ARDS. However, recent studies in murine models suggest that CP may be synthesised in the airways and even alveoli under physiological conditions. Objectives: The aims of this investigation were therefore to identify the source of any increased levels of CP detectable in BALF taken from patients with established ARDS. Methods: Matched BALF and plasma samples taken from patients with ARDS (n = 46) and from controls without lung disease (n = 11) were analysed for CP (132 kD) and plasma specific albumin (ALB, 68 kD) and (α2-macroglobulin (α2-M, 820 kD). Results: All three proteins were increased in BALF taken from patients with ARDS compared to controls (p < 0.01, ALB and CP; p < 0.001, α2-M). When protein levels were expressed as the ratios of BALF: plasma (designated Q), QCP and Qα2-M increased in parallel to QALB (p < 0.001), indicating that all increases were primarily plasma-derived. Their relative coefficients of excretion (RCE: QCP/QALB and Qα2-M/QALB) demonstrated that the larger molecular weight protein, α2-M, gave the best discrimination between patients with ARDS and normal controls (0.85 vs. 0.04; p < 0.01), indicating that this was the most sensitive marker of alveolar-capillary permeability. Conclusions: Increased levels of CP in BALF from patients with ARDS are mainly attributable to plasma exudation.