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Introduction: The relationship between driving pressure (DP) and mortality has not been specifically examined in patients with extrapulmonary acute respiratory distress syndrome (ARDS). Given that outcomes in extrapulmonary ARDS may be largely determined by extrapulmonary multiorgan dysfunction, and that increased chest wall elastance may limit the utility of DP as a surrogate for lung stress, we hypothesized that the association between DP and mortality would be weaker—or even absent—in extrapulmonary ARDS compared to pulmonary ARDS. This study aimed to assess whether the etiology of ARDS modifies the relationship between DP and mortality. Methods: In this prospective cohort study, 172 patients with ARDS requiring invasive mechanical ventilation (IMV) were enrolled and classified as having either pulmonary (n = 82) or extrapulmonary (n = 90) ARDS by three independent intensivists. Respiratory mechanics, including DP, were measured within 24 hours of intubation at a tidal volume of 6.5 ± 0.7 mL/kg predicted body weight. The primary outcome was 90-day mortality. Multivariable Cox regression models were used to assess the interaction between ARDS cause (pulmonary vs. extrapulmonary) and DP on 90-day mortality. Results: Among the 172 patients, 36.3% died within 90 days. Ninety-day mortality tended to be lower in extrapulmonary compared to pulmonary ARDS (30.0% vs. 39.0%, P=0.08). The association between DP and 90-day mortality (HR, 1.13; 95% CI, 1.07–1.21; P < 0.001) varied by ARDS cause (P = 0.04 for interaction), after adjusting for age, PaO2/FiO2, and Sequential Organ Failure Assessment (SOFA) score. Elevated DP was independently associated with increased 90-day mortality in pulmonary ARDS (HR, 1.25; 95% CI, 1.14–1.37; P < 0.001), but not in extrapulmonary ARDS (HR, 1.08; 95% CI, 0.95–1.22; P = 0.207), in which the SOFA score was the only significant predictor of mortality (HR, 1.27; 95% CI, 1.07–1.52; P = 0.008). Conclusions: Our findings suggest that, among ARDS patients receiving IMV, the association between DP and 90-day mortality differs by ARDS etiology, with elevated DP linked to increased risk only in pulmonary ARDS. These results may support a personalized, etiology-specific approach to mechanical ventilation.