Background In light of the pressure to reduce unnecessary healthcare expenditure in the current economic climate, a systematic review that assesses evidence of cost effectiveness of adherence-enhancing interventions would be timely. Objective Our objective was to examine the cost effectiveness of adherence-enhancing interventions compared with care as usual in randomised controlled trials, and to assess the methodological quality of economic evaluations. Methods MEDLINE, PsycInfo, EconLit and the Centre for Reviews and Dissemination databases were searched for randomised controlled trials reporting full economic evaluations of adherence-enhancing interventions (published up to June 2013). Information was collected on study characteristics, cost effectiveness of treatment alternatives, and methodological quality. Results A total of 14 randomised controlled trials were included. The quality of economic evaluations and the risk of bias varied considerably between trials. Four studies showed incremental cost-effectiveness ratios (ICERs) below the willingness-to-pay threshold. Few studies seemed to evaluate interventions that successfully changed adherence. Conclusions Only 14 randomised controlled trials examined the cost effectiveness of adherence interventions. Despite that some studies showe favourable ICERs, the overall quality of studies was modest and the economic perspectives applied were frequently narrow. To demonstrate that adherence interventions can be cost effective, we recommend that proven-effective adherence programmes are subjected to comprehensive economic evaluations.