OBJECTIVES:  Behavioral economic studies have suggested that people may place lower value on free goods, an argument used to justify copayments or coinsurance by insurers. The purpose of this study was to examine the effect of zero cost sharing compared to usual cost sharing on medication adherence or persistence. METHODS:  A systematic literature review was performed using Medline, EMBASE, CINAHL, IPA, Cochrane Library, Scopus, Web of Knowledge, PsychINFO, and Clinicaltrials.gov. Included original articles were English language comparative studies with cost as the main exposure. Each article was assessed by two independent reviewers; disagreements were resolved by consensus. Data on study design, population, intervention, adherence/persistence outcomes, and study quality were abstracted. RESULTS:  The search identified 1941 unique records meeting preliminary inclusion; 19 articles met full inclusion criteria representing 16 independent studies. Two studies were randomized controlled trials (RCTs) with superior methodological quality. Most studies were conducted in the United States and involved a payer-based program or intervention. Among studies using self-reported measures, zero cost sharing significantly decreased cost-related non-adherence, but only had a small negative effect on overall non-adherence. In observational studies, zero cost sharing was associated with sustained or small increases in adherence. Among the RCTs, zero cost sharing had a positive effect on adherence in one study with an insurance policy change, and no effect in one study with an incentive-based program. Overall, few studies evaluated the effect of zero cost sharing on adherence with high methodological quality. Increases in adherence were small and may be related to the program design and population demographics. CONCLUSIONS: No important differential zero price effect could be identified in this literature. Insurers should carefully consider that cost sharing may have a small negative impact on medication adherence, potentially impacting those with cost-related non-adherence most.