Rationale: Fibrin impairs surfactant function in vitro, and inhibition of fibrinolysis by plasminogen activator inhibitor (PAI-1) is thought to promote fibrin accumulation in Acute Lung Injury (ALI). This has led to speculation that impaired PAI-1 and fibrin accumulation should protect lung function in ALI. We tested this hypothesis by investigating ALI severity in fibrinogen deficient (Fgn-/-) and PAI-1 deficient (PAI-1-/-) mice. Methods: PAI-1-/-, C57BL/6, Fgn-/-, and Fgn+/- females were anesthetized and allowed to aspirate 4µL/gm of hydrochloric acid (pH 1.0), then re-anesthetized and connected to a ventilator 48 hours later. Naïve C57BL/6 and Fgn+/- females served as controls. Following deep inflation (DI), forced oscillations were delivered periodically over 8 min to measure changes in elastance (H) as a surrogate of lung derecruitment, at positive end-expiratory pressures (PEEP) of 6, 3, and 1cmH₂O. Results: Increases in H following DI in acid-injured mice were greater than naïve strain-matched controls. Increases in H were no different between injured PAI-1-/- and C57BL/6, or between injured Fgn-/- and +/- mice, at any PEEP. Pressure-volume curves were no different between injured groups. Total lung fibrin was lower in injured PAI-1-/- and Fgn-/- mice relative to injured C57BL/6 and Fgn+/- mice, respectively, but indices of permeability were no different between strains. Conclusions: Unexpectedly, neither fibrin nor PAI-1 deficiency protect lung mechanical function in mice with acid-induced ALI. We speculate that in vivo lung function may be more closely tied to permeability and alveolar protein in general, rather than being linked specifically to fibrin.