Background <p>Diffuse alveolar damage (DAD) represents the hallmark histopathological feature of acute respiratory distress syndrome (ARDS); however, its prognostic significance remains unclear. This study aimed to evaluate the associations between the chronological phases of histologically confirmed DAD and clinical outcomes in patients with ARDS.</p> Methods <p>In this retrospective study, we included patients diagnosed with ARDS who underwent open lung biopsy between January 2002 and December 2025 or transbronchial lung cryobiopsy between January 2017 and December 2025. Rapid progression was defined as the presence of the proliferative phase within 7&#xa0;days or the fibrotic phase within 21&#xa0;days from ARDS diagnosis to lung biopsy.</p> Results <p>A total of 90 patients were included in the analysis. No significant differences were observed in 28-day mortality (36.5% vs. 43.5%, <i>p</i> = 0.556) or 60-day mortality (63.5% vs. 69.9%, <i>p</i> = 0.601) between patients in the proliferative and fibrotic phases. In contrast, patients with rapid progression demonstrated significantly higher 28-day mortality (47.9% vs. 23.8%, <i>p</i> = 0.018) and 60-day mortality (72.9% vs. 50.0%, <i>p</i> = 0.025) than those without rapid progression. Multivariable analysis identified rapid progression as an independent predictor of 60-day mortality (hazard ratio, 2.274; <i>p</i> = 0.014). Furthermore, patients with rapid progression had significantly lower PaCO₂ levels prior to lung biopsy (43.4 ± 11.2 vs. 51.2 ± 21.1&#xa0;mmHg, <i>p</i> = 0.013). Pneumothorax was the most common biopsy-related complication, occurring in 17.8% of patients.</p> Conclusion <p>Rapid progression of DAD was associated with significantly poorer clinical outcomes, and patients with rapid progression had significantly lower PaCO₂ before lung biopsy. Larger controlled studies and additional physiological investigations are warranted to validate these findings.</p>