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Delirium is a common complication in intensive care unit (ICU) patients, and it can significantly increase the length of hospital stay and cost. Dexamethasone is widely used in various inflammatory diseases and must be used with caution in critically ill patients. Previous studies have shown that the effect of corticosteroid use on the development of delirium in critically ill patients is still controversial, and there is inconclusive conclusion about the effect of dexamethasone on delirium in such patients. Therefore, this study aimed to confirm the effect of dexamethasone use and the dose on the incidence of delirium and patient prognosis in critically ill patients through a large cohort study. A retrospective cohort study was conducted using data extracted from the Medical Information Mart for Intensive Care III database, which is a large and freely available database of all 46,476 patients who visited Beth Israel Deaconess Medical Center in Boston, Massachusetts, USA and were admitted to the ICU between 2001 and 2012. The primary outcome was the development of delirium, using multivariate logistic regression analysis to reveal the relationship between dexamethasone and delirium. Secondary endpoints were in-hospital mortality, ICU mortality, total length of stay, and length of ICU stay, and the relationship between dexamethasone and prognosis was assessed with Cox proportional hazards models. Propensity score matching with 1:1 grouping was used to eliminate the effect of confounders on both cohorts. The locally weighted scatter plot smoothing technique was used to investigate the dose correlation between dexamethasone and outcomes, subgroup analysis was used to account for heterogeneity, and different correction models and propensity matching analysis were used to eliminate potential confounders. Finally, 38,509 patients were included, and 2204 (5.7%) used dexamethasone. No significant statistical difference was observed in basic demographic information after propensity score matching between the two study groups. A significantly higher incidence of delirium (5.0% versus 3.4%, P < 0.001), increased in-hospital mortality (14.9% versus 10.3%, P < 0.001), ICU mortality (9.0% versus 7.5%, P = 0.008), and longer length of stay and ICU stay were observed in patients taking dexamethasone compared with those not taking dexamethasone. Multivariate logistic and Cox regression analyses confirmed that dexamethasone was significantly associated with delirium (adjusted odds ratio = 1.48, 95% confidence interval [CI] = 1.09-2.00, P = 0.012), in-hospital mortality (adjusted hazard ratio = 1.19, 95% CI = 1.02-1.40, P = 0.032), and ICU mortality (adjusted hazard ratio = 1.62, 95% CI = 1.22-2.15, P = 0.001). Compared with critically ill patients using high-dose dexamethasone, the risk of delirium was lower in the dose less than the 10 mg group, and patients using 10-14 mg may be associated with a lower risk of in-hospital death and the least ICU mortality, length of hospital stay, and ICU stay. This study demonstrated that the use of dexamethasone in critically ill patients exacerbated the occurrence of delirium while increasing the risk of in-hospital death, ICU death, and length of hospital stay, with a lower risk of delirium and a shorter total length of hospital stay with low-dose dexamethasone than with larger doses. [ABSTRACT FROM AUTHOR]