Rationale: Platelets are believed to contribute to acute respiratory distress syndrome (ARDS) pathogenesis through inflammatory coagulation pathways. We recently reported that leucine-rich repeat-containing 16A (LRRC16A) modulates baseline platelet counts to mediate ARDS risk.Objectives: To examine the role of LRRC16A in ARDS survival and its mediating effect through platelets.Methods: A total of 414 cases with ARDS from intensive care units (ICUs) were recruited who had exome-wide genotyping data, detailed platelet counts, and follow-up data during ICU hospitalization. Association of LRRC16A single-nucleotide polymorphisms (SNPs) and ARDS prognosis, and the mediating effect of SNPs through platelet counts were analyzed. LRRC16A mRNA expression levels for 39 cases with ARDS were also evaluated. Patients with ΔPLT were associated with favorable ARDS outcomes. Mediation analysis indicated that the SNP prognostic effect was mediated through ΔPLT within 28 days (28-day survival: HR Indirect , 0.937; 95% CI, 0.91820.957; P = 0.0009, 11.53% effects mediated; 60-day survival: HR Indirect , 0.919; 95% CI, 0.90120.936; P = 0.0001, 14.35% effects mediated). Functional exploration suggested that this SNP reduced LRRC16A expression at ICU admission, which was associated with a lesser ΔPLT during ICU hospitalization.Conclusions: LRRC16A appears to mediate ΔPLT after ICU admission to affect the prognosis in patients with ARDS.