BackgroundVentilator-associated pneumonia (VAP) is a frequent intensive care unit (ICU) complication linked to prolonged ventilation, extended ICU and hospital stays, increased costs, and higher mortality. Current guidelines recommend light sedation with dexmedetomidine (DEX) or propofol for ventilated adults. Although DEX has shown anti-inflammatory effects in animal models, its impact on VAP outcomes remains unclear. This study aims to investigate the association between DEX administration and 28-day mortality in patients with VAP.MethodsThis retrospective cohort study enrolled VAP patients from the Medical Information Mart for Intensive Care (MIMIC) (version 3.0) database, categorized into DEX-treated and non-DEX groups during ICU admission. The primary outcome was 28-day mortality. Secondary outcomes included ICU, in-hospital mortality. Kaplan-Meier (KM) survival curves with log-rank tests and Cox proportional hazards models evaluated the association between DEX use and mortality outcomes. To adjust for baseline differences, 1:1 propensity score matching (PSM) was applied. Interaction and subgroup analyses further examined result consistency.ResultsData from 1,753 patients were analyzed, comprised 901 in the DEX group and 852 in the non-DEX group. The analysis of KM curves revealed a significantly lower 28-day mortality rate in the DEX group compared to the non-DEX group. After adjusting for multiple confounding factors, the Cox regression model demonstrated a significant protective impact of DEX-use on the risk of 28-day mortality in patients with VAP, with hazard ratios (HR) of 0.54 (95% confidence interval (CI): 0.43–0.67, p < 0.001). PSM analysis confirmed these results, showing HR of 0.81 (95% CI: 0.65–0.99, p = 0.044). No interactions were observed between DEX-use and 28-day mortality across stratified variables.ConclusionDEX administration during the ICU stays was associated with improved outcomes in critically ill patients with VAP. The results need to be verified in randomized controlled trials.