Treatment guidelines have recently become more definitive regarding the optimal timing for initiation of combination antiretroviral therapy (ART) in the setting of an acute AIDS-related opportunistic infection (OI). These recent changes reflect new data from a prospective, randomized study and several retrospective studies, all of which support earlier initiation of ART during an OI. These studies focus on OIs for which effective antimicrobial therapy exists. For AIDS-related conditions that lack effective antimicrobial therapy, there are few studies to help inform the optimal timing to initiate ART, but most clinicians initiate ART early, as little else can be offered to these patients. For patients with HIV admitted for non-AIDS-related conditions, there are few data that directly address the optimal timing for ART. Initiating ART in the hospitalized patient can be challenging and requires a well-coordinated multidisciplinary team with expertise in ART management.