This chapter reviews of the epidemiology, diagnosis, and treatment of the major psychiatric aspects of HIV infection, in addition to somatic symptoms such as sleep disorder, fatigue, sexual dysfunction, and HIV-associated lipodystrophy, all of which have substantial quality of life impact. Benzodiazepines should be avoided in patients with cognitive impairment and delirium. Delirium is common among hospitalized HIV/AIDS patients. Most studies documenting rates of delirium were conducted in the pre-highly active antiretroviral therapy (HAART) era and were restricted to subsets of patients seen in psychiatric consultation. Sleep disorders, primarily insomnia disorders, are prevalent in the HIV-infected population. Hepatitis C virus (HCV) infection is increasingly recognized as a significant comorbid condition that affects the clinical outcome of patients with substance abuse disorders and HIV disease. Fatigue is common among patients with HIV/AIDS and may contribute to impairment in physical function and disability. With the advent of nucleoside analog reverse transcriptase inhibitors (NRTIs) (e.g., zidovudine), nonnucleoside analog reverse transcriptase inhibitors (NNRTIs) (e.g., efavirenz), and PIs (e.g., indinavir) as part of HAART, there has been heightened interest in the issue of drug interactions in the context of HIV psychopharmacology. HIV-associated lipodystrophy is an increasingly recognized complication of prolonged treatment with HAART that may have significant impact on the psychological well-being and quality of life of those affected.