Peptides which inhibit MARCKS protein dramatically reduce sudden neutrophil infiltration in the lung in response to stress. ARDS was induced in mice by intratracheal instillation of LPS. After treatment with inhaled aerosolized anti-MARCKS peptides (BIO-11006 or BIO-10901) with treatment started as long as 36 hrs post LPS instillation (LPS: 5 ?g Escherichia coli endotoxin; 2 mg/kg in 50 ?l of PBS). Animals were monitored for behavior, at 48 hrs post LPS instillation, after either two administrations of peptide or saline control. At 72 hrs post LPS instillation, animals were sacrificed and lungs lavaged, and total leukocytes, neutrophils, inflammatory cytokines (KC [murine IL-8 equivalent], TNF?) were measured. In addition, NF-?B activation and cytokine gene expression were measured in whole lung homogenates, and lungs fixed for histological examination. Administration of either peptide produced similar effects: Mouse behavior, breathing effort and rate, piloerection, ptosis, “hunching”, and activity returned to normal after 2 treatments 12 hrs apart with the inhaled peptide, whereas untreated animals remained moribund. Either peptide caused significant decreases in lung total leukocytes and neutrophils, as well as protein and gene expression of inflammatory cytokines. Activation of NF-?B also was inhibited by peptide inhalation. The results suggest that inhaled aerosolized peptide inhibitors of MARCKS protein could provide therapeutic benefit in patients with ARDS, and might even reverse disease progress if administered after established ARDS.