Despite the substantial benefits of combination antiretroviral therapy (ART), a significant proportion of HIV-infected individuals still present with advanced disease and active AIDS-related opportunistic infections (OIs). The weight of evidence from recent studies supports the early initiation of ART (ie, within 2 weeks of initiating treatment for the acute OIs). Initiating ART early in acutely ill patients can reduce AIDS-related progression and death. Early ART has not been associated with increased rates of immune reconstitution inflammatory syndrome in prospective studies of non-tuberculosis OIs, although this concern is frequently cited as a reason to delay ART. Nor has early ART been associated with increased adverse outcomes. Nonetheless, initiating ART early in acute care settings can be challenging to implement and requires a well-coordinated multidisciplinary team with expertise in ART management.