Since the advent of highly active antiretroviral therapy in 1996, we have seen dramatic changes in morbi-mortality rates from human immunodeficiency virus-positive patients. If on the one hand, the immunologic preservation-associated with the use of current antiretroviral therapy markedly diminishes the incidence of opportunistic infections, on the other hand it extended life expectancy of human immunodeficiency virus-infected individuals similarly to the general population. However, the management of critically ill human immunodeficiency virus-infected patients remains challenging and troublesome for practicing clinician. Sepsis - a complex systemic inflammatory syndrome in response to infection - is the second leading cause of intensive care unit admission in both human immunodeficiency virus-infected and uninfected populations. Recent data have emerged describing a substantial burden of sepsis in the infected population, in addition, to a much poorer prognosis in this group. Many factors contribute to this outcome, including specific etiologies, patterns of inflammation, underlying immune dysregulation related to chronic human immunodeficiency virus infection and delays in prompt diagnosis and treatment. This brief review explores the impact of sepsis in the context of human immunodeficiency virus infection, and proposes future directions for better management and prevention of human immunodeficiency virus-associated sepsis.