We investigated serum ferritin levels as a predictor of the acute respiratory distress syndrome (ARDS) because: (1) proinflammatory cytokines, which are implicated in ARDS, increase ferritin synthesis; and (2) oxidative stress in patients at risk for ARDS might liberate iron from ferritin, accelerating toxic hydroxyl radical (.OH) formation. Serum ferritin levels measured by radioimmunoassay (RIA) were greater in 75 patients at risk for ARDS (women, p < 0.0001; men, p < 0.0001) and 8 patients with ARDS (women, p = 0.001; men, p = 0.0009) than in healthy control subjects. Serum ferritin levels were also greater in female (p = 0.003) and male (p = 0.003) at-risk patients who developed ARDS than in patients who did not develop ARDS. In women, a value exceeding 270 ng/ml predicted ARDS with an 83% sensitivity, 71% specificity, 67% positive, and 86% negative predictive value. In men, a value exceeding 680 ng/ml predicted ARDS with a 60% sensitivity, 90% specificity, 75% positive, and 82% negative predictive value. Serum ferritin levels did not correlate with C-reactive protein levels, were not different in medical or surgical at-risk patients, and were not accounted for by liver disease. Evaluating serum ferritin levels in at-risk patients may help predict the development of ARDS and thereby improve study and treatment of ARDS. Elevated serum ferritin levels may also regulate the participation of iron in the oxidative responses that contribute to ARDS.