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Sepsis, an important cause of hospital mortality, continues to be a diagnostic and therapeutic challenge. To define more clearly the impact of encephalopathy on the course of sepsis, the various clinical signs of sepsis, blood culture results, and mortality rates were examined in relation to mental status in septic patients. Patients were classified as having an acutely altered mental status due to sepsis (AAMS), preexisting altered mental status (PAMS), or normal mental status (NMS). Twenty-three (307/1333) percent of the study patients had an acutely altered sensorium secondary to sepsis. Patients with AAMS had a higher mortality (49%) than patients with PAMS (41%) or patients with NMS (26%) (p < .000001). Multivariate analysis disclosed that altered mental status, hypothermia, hypotension, thrombocytopenia, and the absence of shaking chills were independent predictors of increased mortality in the sepsis syndrome. Patients with Gram-negative bacteremia (28%) were as likely to have AAMS as patients with Gram-positive bacteremia (25%) or patients with negative blood cultures (23%). In summary, alterations in mental status are common in septic patients, and are associated with significantly higher mortality.