Suboptimum medication adherence is common in the United States and leads to serious negative health consequences but may respond to intervention. To assess the comparative effectiveness of patient, provider, systems, and policy interventions that aim to improve medication adherence for chronic health conditions in the United States. Eligible peer-reviewed publications from MEDLINE and the Cochrane Library indexed through 4 June 2012 and additional studies from reference lists and technical experts. Randomized, controlled trials of patient, provider, or systems interventions to improve adherence to long-term medications and nonrandomized studies of policy interventions to improve medication adherence. Two investigators independently selected, extracted data from, and rated the risk of bias of relevant studies. The evidence was synthesized separately for each clinical condition; within each condition, the type of intervention was synthesized. Two reviewers graded the strength of evidence by using established criteria. From 4124 eligible abstracts, 62 trials of patient-, provider-, or systems-level interventions evaluated 18 types of interventions; another 4 observational studies and 1 trial of policy interventions evaluated the effect of reduced medication copayments or improved prescription drug coverage. Clinical conditions amenable to multiple approaches to improving adherence include hypertension, heart failure, depression, and asthma. Interventions that improve adherence across multiple clinical conditions include policy interventions to reduce copayments or improve prescription drug coverage, systems interventions to offer case management, and patient-level educational interventions with behavioral support. Studies were limited to adults with chronic conditions (excluding HIV, AIDS, severe mental illness, and substance abuse) in the United States. Clinical and methodological heterogeneity hindered quantitative data pooling. Reduced out-of-pocket expenses, case management, and patient education with behavioral support all improved medication adherence for more than 1 condition. Evidence is limited on whether these approaches are broadly applicable or affect longterm medication adherence and health outcomes. Agency for Healthcare Research and Quality.