BACKGROUND: US health plans are adopting benefit designs that shift greater financial burden to patients through higher deduct-ibles, additional copay tiers, and coinsurance. Prior systematic reviews found that higher cost was associated with reductions in both appropriate and inappropriate medications. However, these reviews were conducted prior to contemporary benefit design and medica-tion utilization.OBJECTIVE: To assess the relationship and factors associated with cost-sharing and (1) medication adherence, (2) clinical out-comes, (3) health care resource utilization (HRU), and (4) costs.METHODS: A systematic review of literature published between January 2010 and August 2020 was conducted to identify the relation-ship between cost-sharing and medication adherence, clinical outcomes, HRU, and health care costs. Data were extracted using a standardized template and were synthe-sized by key questions of interest.RESULTS: From 1,995 records screened, 79 articles were included. Most studies, 71 of 79 (90%), reported the relationship between cost-sharing and treatment adherence, per-sistence and/or discontinuation; 16 (20%) reported data on cost-sharing and HRU or medication initiation, 11 (14%) on cost -sharing and health care costs, and 6 (8%) on cost-sharing and clinical outcomes. The majority of publications found that, regard-less of disease area, increased cost-sharing was associated with worse adherence, per-sistence, or discontinuation. The aggregate data suggested the greater the magnitude of cost-sharing, the worse the adherence. Among studies examining clinical outcomes, cost-sharing was associated with worse out-comes in 1 study and the remaining 3 found no significant differences. Regarding HRU, higher-cost-sharing trended toward decreased outpatient and increased inpatient utilization. The available evidence suggested higher cost-sharing has an overall neutral to negative impact on total costs. Studies evaluating elimination of copays found either decreased or no impact in total costs.CONCLUSIONS: The published literature shows consistent impacts of higher cost sharing on initiation and continuation of medications, and the greater the cost -sharing, the worse the medication adher-ence. The evidence is limited regarding the impact of cost-sharing on clinical outcomes, HRU, and costs. Limited evidence suggests increased cost-sharing is associated with more inpatient care and less outpatient care; however, a neutral to no differ-ence was suggested for other outcomes. Although increased cost-sharing is intended to decrease total costs, studies evaluating reducing or eliminating cost-sharing found that total costs did not rise. Today's growing cost-containment environment should carefully consider the broader impact cost-sharing has on treatment adher-ence, clinical outcomes, resource use, and total costs. It may be that cost-sharing is a blunt, rather than precise, tool to curb health care costs, affecting both necessary and unnecessary health care use.