The Center for Adherence Support Evaluation (CASE) Adherence Index, a simple composite measure of self-reported antiretroviral therapy (ART) adherence, was compared to a standard three-day self-reported adherence measure among participants in a longitudinal, prospective cross-site evaluation of 12 adherence programs throughout the United States. The CASE Adherence Index, consisting of three unique adherence questions developed for the cross-site study, along with a three-day adherence self-report were administered by interviews every three months over a one-year period. Data from the three cross-site adherence questions (individually and in combination) were compared to three -day self-report data and HIV RNA and CD4 outcomes in cross-sectional analyses. The CASE Adherence Index correlated strongly with the three-day self-reported adherence data (p < 0.001) and was more strongly associated with HIV outcomes, including a 1-log decline in HIV RNA level (maximum OR = 2.34; p < 0.05), HIV RNA < 400 copies/ml (maximum OR = 2.33; p < 0.05) and performed as well as the three-day self-report when predicting CD4 count status. Participants with a CASE Index score >10 achieved a 98 cell mean increase in CD4 count over 12 months, compared to a 41 cell increase for those with scores < or =10 (p < 0.05). The CASE Adherence Index is an easy to administer instrument that provides an alternative method for assessing ART adherence in clinical settings.