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We investigated whether high prolactin levels were associated with delirium in septic patients because neuropsychiatric disorders are frequently associated with hyperprolactinemia.Prolactin levels were measured daily for 4 days in 101 patients with sepsis. Delirium was assessed using the Richmond Agitation Sedation Scale and the Confusion Assessment Method in the ICU.Delirium developed in 79 patients (78%) and was more common in patients older than 65 years. Prolactin levels were higher in patients with delirium than in those without over the 4 days of observation (P = .032). In patients with delirium, higher prolactin levels were associated with a lower incidence of nosocomial infection (P = .006). Multivariable logistic regression showed that the Sequential Organ Failure Assessment score at intensive care unit admission (odds ratio, 1.24; 95% confidence interval, 1.04–1.48; P = .002) and the combined effect of prolactin levels with age (odds ratio, 1.018; 95% confidence interval, 1.01–1.031; P = .006) were associated with the development of delirium.High prolactin levels may be a risk factor for delirium in septic patients.