The goal of palliative care is to minimize and prevent suffering and maximize physical function and quality of life in patients with serious illness. In the early years of the AIDS epidemic in developed countries, prognosis was poor and palliative care was often inseparable from HIV care. Despite the advent of effective antiretroviral therapy and its availability in developed countries, patients with HIV disease still present many palliative care challenges and opportunities. The cases of 3 HIV-infected patients who embody these challenges will be presented in this article: an older patient with numerous medical comorbidities, chronic pain, and severely impaired physical function; a patient with psychiatric illness and substance abuse, difficulties with adherence to antiretroviral therapy and retention in HIV primary care, and cryptococcal meningitis; and a patient with stable HIV disease and hepatitis C virus-related liver failure. These cases are being presented to stimulate a discussion between HIV and palliative care practitioners about potential areas of clinical and research collaboration.