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Abstract: Purpose: Critical care outcomes among HIV-infected patients have improved because of advances in HIV therapy and general improvements in intensive care unit (ICU) management. There is a high co-occurrence of drug and alcohol dependence among HIV-infected patients, and the independent role of drug and alcohol dependence among patients with and without HIV infection in outcomes of critical illness is unclear. Materials and methods: We analyzed a prospectively collected database of 7015 index ICU admissions at 2 teaching hospitals between January 1999 and January 2006. The ICU diagnoses were determined from prospective chart review and classified according to the dictionary of diagnoses developed by the Intensive Care National Audit and Research Council. We used logistic regression to determine the independent association of drug and alcohol dependence as well as HIV infection with in-hospital mortality. Covariates that were adjusted for included acute drug overdose, Acute Physiology and Chronic Health Evaluation II score, age, sex, hospital site, and socioeconomic variables. Results: Of all patients, 4.4% (309 of 7015) were HIV infected; and of these, 56% (173 of 309) had a history of drug and alcohol dependence, whereas only 7.4% (502 of 6706) of the HIV-negative group had a history of drug and alcohol dependence. Drug and alcohol dependence was not independently associated with hospital mortality in either the model including all admissions (adjusted odds ratio [AOR] 0.80; 95% confidence interval [CI] 0.62-1.03) or the model including pneumonia and sepsis admissions only (AOR 0.92; 95% CI 0.59-1.41). Infection with HIV was independently associated with hospital mortality (AOR 2.16; 95% CI 1.60-2.93). Conclusions: Although HIV infection is associated with increased hospital mortality, drug and alcohol dependence is not associated with an increased hospital mortality independent of HIV infection. [Copyright &y& Elsevier]