The independent effects of chronic disease, age, severity of illness, lung injury score (LIS) and etiology, and preceding nonpulmonary organ-system dysfunction (OSD) on the outcome of acute lung injury (ALI) have not been examined in an exclusively medical-intensive-care-unit (MICU) population. Therefore, 107 consecutive MICU patients with ALI (76% with acute respiratory distress syndrome [ARDS]) were prospectively investigated. The impact of comorbidities, age > 65 yr, acute physiology score (APS), LIS, etiology of ALI, and OSD on hospital survival were studied. The overall mortality was 62 of 107 patients (58%), including 47 (58%) with ARDS. With univariate analysis, age > 65 yr, organ transplantation, human immunodeficiency virus (HIV) infection, active malignancy, chronic steroid use, and a septic or aspiration-related etiology of ALI were associated with a ≥ 1.2-fold greater relative risk (RR) of hospital mortality. With multiple logistic regression, independent predictors of hospital death were age > 65 yr, organ transplantation, HIV infection, cirrhosis, active malignancy, and sepsis. APS, LIS, aspiration-related etiology of ALI, preceding OSD, and other comorbidities were not independently predictive of hospital death. Multivariate analysis of the ARDS cohort showed similar results, although cirrhosis and malignancy did not reach statistical significance. We conclude that comorbid conditions, older age, and sepsis etiology are independent predictors of hospital death in exclusively MICU patients with ALI (76% of whom satisfied criteria for ARDS). These factors should be considered in analyzing studies of new therapies and interpreting trends in mortality for ALI and ARDS.