OBJECTIVES: To assess economic and clinical characteristics of severe comorbidities during inpatient hospitalizations in persons with HIV/AIDS. METHODS: The Agency for Healthcare Research and Quality (AHRQ) Healthcare Cost and Utilization Project (H-CUP) Nationwide Inpatient Sample (NIS) was used in this retrospective database study spanning 2005-2009.  Inpatient cases of HIV/AIDS among persons 18 years of age or older were used as inclusion criteria. Key clinical comorbidities analyzed included organ insufficiency/failure, cancers, heart failure, pulmonary circulation disorders, coagulopathies, fluid/electrolyte disorders, and wasting syndromes/weight loss. Outcomes of inpatient mortality and hospital charges were assessed via multivariate logistic and gamma regression, respectively, after controlling for comorbidities, patient demographics, hospital characteristics, payer, and lengths of stay. RESULTS: There were 1,227,718 overall inpatient cases of HIV/AIDS from 2005-2009 in the United States, averaging 44.8 (±10.7) years of age, 6.7 (±9.0) days for length of stay, and inpatient charges of $36,004 (±59,303). Mortality occurred in 41,609 cases, constituting 3.4% of all HIV/AIDS hospitalizations and averaging 47.0 (±11.1) years of age, 13.4 (±17.4) days for length of stay, and inpatient charges of $104,558 (±136,254). Fluid/electrolyte disorders occurred in 57.1% of mortality cases, followed by sepsis/septicemia (39.3%), coagulopathies (23.8%), renal failure (19.4%) wasting syndrome/weight loss (18.4%), liver disease (16.2%) heart failure (9.7%), lymphoma (6.6%), metastatic cancer (3.3%), pulmonary circulation disorders (2.9%), and solid tumors (2.8%). Regression analyses found that increased mortality and charges were associated with each aforementioned comorbidity except wasting syndromes/weight loss.  Significant (p≤0.05) odds ratios were observed for inpatient mortality ranging from 1.17 (renal failure) to 8.06 (sepsis/septicemia) and exponentiated beta-coefficients for charges ranging from 1.03 (liver disease) to 1.33 (sepsis/septicemia). Various cancers were associated with substantially worse outcomes. CONCLUSIONS: An increased understanding of severe comorbidities in HIV/AIDS is of continued importance within hospital settings. Sepsis/septicemia and cancer is particularly associated with increased inpatient mortality and charges.