Abstract RATIONALE: Rapidly improving acute respiratory distress syndrome (RIARDS) is a subgroup of ARDS in which hypoxemia significantly improves within 24 hours after initiation of mechanical ventilation. RIARDS has been described in up to 20% of all-cause ARDS cases in an observational cohort, and has been associated with the hypoinflammatory ARDS phenotype. The purpose of this study was to define the clinical characteristics and outcomes of RIARDS among patients with sepsis-associated ARDS, and to validate its association with inflammatory subphenotypes within this cohort. METHODS: We analyzed data from 787 endotracheally intubated patients who met Berlin criteria for ARDS within three days of ICU admission and were enrolled in a prospective observational cohort of critically ill patients with sepsis. RIARDS was defined according to previous studies as improvement of hypoxemia determined by either (i) PaO2:FIO2 > 300 or SpO2:FIO2 > 315 on the day following diagnosis of ARDS (day 2); or (ii) unassisted breathing by day 2 and for the next 48 hours (defined as absence of endotracheal intubation on day 2 through day 4). Participants who did not meet RIARDS criteria were categorized as persistent ARDS. Plasma biomarkers were measured on samples collected on the day of ICU admission, and ARDS subphenotypes were determined using a published parsimonious algorithm using IL-8, sTNFR1, and serum bicarbonate. Two-group comparisons between RIARDS and persistent ARDS were done using the Mann-Whitney U test or Fisher's exact test. RESULTS: Of the 787 enrolled patients, 70 (9%) met criteria for RIARDS. Participants with RIARDS had a lower prevalence of vasopressors use (17% vs 36%, p=0.003), less severe ARDS (p=0.004), and lower 28-day mortality (50% vs 64%; p=0.028). Compared to persistent ARDS, patients with RIARDS less commonly had sepsis from pneumonia (57% vs 70%, p=0.042) and had lower plateau pressures on the day of ARDS diagnosis (21cmH2O vs 23 cmH2O, p=0.005). Plasma levels of inflammatory biomarkers did not differ between RIARDS and persistent disease, and the hyperinflammatory ARDS phenotype was present in over two-thirds of both groups (86% and 71%, p=0.009, respectively). CONCLUSION: In patients with sepsis-associated ARDS, we detected a lower prevalence of RIARDS than previously reported in all-cause ARDS. Consistent with previous studies, RIARDS was associated with less severe clinical disease and lower mortality. The hyperinflammatory phenotype was equally highly enriched in both RIARDS and persistent ARDS, suggesting that the degree of systematic inflammation may not explain clinical differences between these groups among sepsis-associated ARDS.