Participation in antiretroviral therapy clinical trials (ART-RCTs) offers many advantages including access to new drugs, close monitoring, and cost savings. These same benefits may pose a risk to patients ending ART-RCTs and returning to routine care; as they may experience changes to their drug regimen, decreased monitoring, and new out-of-pocket costs. We aimed to evaluate this transition and determine its effects on viral outcomes and patient perceptions. A retrospective cohort was assembled from participants of naïve ART-RCTs at the University of Pennsylvania between 1 January 2000 and 31 December 2009. Data were collected in the 12 months prior to and after trial completion. Multivariable logistic regression was used to evaluate viral failure rates and to identify factors associated with viral failure. Qualitative interviews were held with a subset of patients. Content analysis was used to identify thematic differences between patients with viral failure and those with viral suppression. In total, 116 patients enrolled in 5 ART-RCTs from 2000 to 2009. Viral failure was observed in 39 patients (34%). Nonwhites, high enrollment CD4 count, and trial completion in 1999-2002 were risk factors for failure. Patients transitioning from ART-RCTs to routine care had a 20% increased odds of failure (Adjusted Odds Ratio 1.20 (95% CI [0.37, 3.88])). Nine patients with viral suppression and three with viral failure in the year after trail completion were interviewed. Suppressed patients were more eager to continue trial participation, nervous about leaving the trial, and felt prepared to return to routine care. In contrast, those with viral failure were less concerned about the transition. These findings suggest that the posttrial period may be a vulnerable time for patients. Patients without a healthy fear of transitioning from ART-RCTs to routine care may be at increased risk of viral failure. Focus should be given to assisting patients during this transition.