Previous microarray-based studies of acute respiratory distress syndrome (ARDS) were performed using various models to mimic disease pathogenesis. The complexity of the pathophysiologic response to direct or indirect lung injury in ARDS is difficult to reconstruct in experimental conditions. Thus, direct analysis of ARDS patient blood may provide valuable information. We investigated genome-wide gene expression profiles in paired whole blood samples from ARDS patients (n=8) during the acute-stage (within three days of diagnosis) and recovery-stage of ARDS (around ICU discharge). Among 126 differentially expressed genes, peptidase inhibitor 3 (PI3, encoding elafin, a potent neutrophil elastase inhibitor) had the largest fold-change (-3 fold-change) in expression, indicating down-regulation during the acute-stage of ARDS. We further examined plasma PI3 levels in 40 ARDS patients and 23 at-risk controls from the same cohort. There was a coincidence of the microarray findings of lower PI3 gene expression with the lower plasma PI3 during the acute-stage. The plasma PI3 levels were statistically significant different among pre-diagnosis, day of diagnosis, and post-diagnosis groups (ANOVA, p = 0.001), with a trend of decreasing from pre- to post-diagnosis group. The time course of plasma PI3 decrease is well correlated with the course of early ARDS development (Pearson correlation coefficient: -0.52, p = 0.0006). Considering PI3 can covalently binding to extracellular matrix in lung, circulating PI3 may provide a useful clinical marker for monitoring the early development of ARDS and may have implications for ARDS treatment.