Due to the toxicities of available antiretroviral therapy (ART) in the early 2000s, some healthcare providers and patients theorized that it may be beneficial to take breaks from taking ART. The Strategies for Management of Anti-Retroviral Therapy (SMART) study (initiated by the CPCRA and completed by the INSIGHT network) enrolled 5,472 participants in 33 countries from 2002 to 2006. SMART compared two ART management strategies: continuous use (viral suppression) versus episodic use (drug conservation). SMART results showed that episodic ART guided by CD4 count significantly increased the risk of opportunistic disease or death from any cause, as compared with continuous ART. Episodic ART did not reduce the risk of adverse events that have been associated with ART. SMART results provided clear and compelling evidence that use of treatment interruptions is deleterious.