OBJECTIVES: The objective of this systematic review was to evaluate the effectiveness of adherence-enhancing interventions for highly active antiretroviral therapy (HAART) in HIV-infected patients in developed countries. METHODS: A systematic literature search was performed (January 2001 to May 2012) in EMBASE, including MEDLINE records, CENTRAL and PsycInfo. Trials meeting the following predefined inclusion criteria were included: adult patients with an HIV infection treated with HAART, an intervention to enhance patient adherence, adherence as the outcome, clinical outcomes, randomized controlled trial (RCT), article written in English or German, patient enrolment after 2001, and trial conducted in World Health Organization (WHO) stratum A. Selection was performed by two reviewers independently. All relevant data on patient characteristics, interventions, adherence measures and results were extracted in standardized tables. The methodological trial quality was evaluated by two reviewers independently. All discrepancies were discussed until a consensus was reached. A meta-analysis could not be performed because of the heterogeneity of trials. RESULTS: In total, 21 trials fulfilled all inclusion criteria. Of 21 trials, only one that examined motivational interviewing for alcohol-dependent patients showed statistically significant results for adherence rates and viral load in favour of the intervention. One trial showed a statistically significant clinical effect of the intervention; however, inconsistent results were presented for adherence depending on the underlying adherence definition. The results of the remaining 19 trials were not statistically significant or were conflicting for adherence and/or clinical outcomes. However, the methodological trial quality was low. CONCLUSIONS: It is not possible to definitively assess the effectiveness of adherence-enhancing interventions. However, it appears that most adherence interventions have no effect.