OBJECTIVES:  To determine the association between copayment, medication adherence and outcomes in patients with Heart failure (HF) and Diabetes Mellitus (DM). METHODS:  A systematic literature review was performed in PubMed, Scopus and Cochrane databases using combinations of 4 sets of predetermined key-words which were: drug cost sharing; clinical and economic outcomes; medication adherence; and chronic disease (HF and DM). The identified studies were independently reviewed by two reviewers against pre-determined inclusion and exclusion criteria. The data of selected studies were extracted by the same two reviewers using a data extraction form developed specifically to address the review issues in hand and consequently were qualitatively synthesized. RESULTS:  Thirty-eight studies were included in the review. Seven and one studies evaluating the relationship between copayment and medication adherence in DM and HF population, respectively, demonstrated an inverse statistically significant association. Concerning the direct effect of copayment changes on outcomes, the scarcity and diversity of data, does not allow us to reach a safe and clear conclusion, although there is some evidence indicating that higher copayments may result in poorer health and economic outcomes. All studies (29) examining the relationship between medication adherence and outcomes, revealed that increased adherence is associated with health benefits in both DM and HF patients. Finally, the majority of studies in both populations, showed that medication adherence was related to lower resource utilization which in turn may lead to lower total healthcare cost. CONCLUSIONS:  The results of our systematic review imply that lower copayments may result in higher medication adherence, which in turn may lead to better health outcomes and lower total healthcare expenses; still there is not strong evidence to demonstrate a direct effect of copayment changes on health and economic outcomes in patients with DM and HF.