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Introduction: Hospital-onset sepsis (HOS) accounts for 10-15% of all hospital-treated sepsis events, with two-fold higher mortality compared to community-onset sepsis (COS). Social vulnerability is associated with increased mortality in sepsis, but these estimates are driven by COS & evidence on the prognostic impact of social deprivation in HOS is lacking. We aimed to examine the population-level association of the Social Vulnerability Index (SVI) with short-term mortality in HOS. Methods: Statewide data were used to identify hospitalizations aged ≥18 years with HOS in Texas from 2020 to 2023. HOS was defined as ICD-10 codes R6520 or R6521 without a present-on-admission indicator. Hospitalizations with COVID-19 were excluded. SVI (a composite measure of socioeconomic status, household characteristics, racial and ethnic minority status, and housing type and transportation, reported on a percentile scale 0-1 [higher values indicate greater vulnerability]) at the zip code level was linked to hospitalization data. Hierarchical logistic models were fit to estimate the association of SVI (modeled as quartiles) with short-term mortality (in-hospital death or discharge to hospice) among hospitalizations with HOS overall and for demographic strata, with sensitivity analyses of ICU admissions, septic shock, and mechanical ventilation. Results: There were 39,965 hospitalizations with HOS (59.5% aged ≥65 years; 47.0% female; 51.7% racial or ethnic minorities; median [IQR] SVI 0.57 [0.33 – 0.80]; ICU admission 85.4%; septic shock 84.1%; mechanical ventilation 33.5%). The short-term mortality among HOS hospitalizations was 51.8% in the top SVI quartile vs. 50.5% in the bottom SVI quartile. On adjusted analyses, the top SVI quartile was associated with an increased short-term mortality overall (adjusted odds ratio 1.15 [95% CI 1.05-1.24]; bottom SVI quartile as reference) and among those aged ≥65 years, females, Whites, ICU admissions, and those with septic shock, or undergoing mechanical ventilation. Conclusions: Higher SVI was associated with increased mortality among patients with HOS. This association was driven by select demographic groups and the more severely ill strata of patients with HOS. Further studies are needed to explore the mechanisms underlying the selective adverse prognostic associations of SVI in HOS.