OBJECTIVES: To systematically evaluate studies assessing the outcomes and economic value of decreased medication dosing frequency. METHODS: We searched the literature from 1998 to 2008 using the MEDLINE database for articles that evaluated the cost-effectiveness of dosing frequency changes and adherence. Only non-English articles were initially excluded; from the identified citations, all abstracts were reviewed; those lacking a clear link between dosing frequency changes, adherence, and costs or cost-effectiveness analysis (CEA) were excluded. The selected articles were thoroughly reviewed and summarized. RESULTS: A total of 168 citations were identified: after exclusions by reviewing the abstracts, 21 were selected and reviewed--18 original studies and three systematic reviews. The articles encompassed several chronic pathologies, e.g., osteoporosis (seven) and hepatitis C (two). Seven of the ten economic studies utilized decision modeling frameworks (usually one-year horizon), where the effect of dosing frequency changes on adherence was not the primary outcome. In most cases, assumptions on adherence changes were used as part of the sensitivity analysis, but lacked support from strong evidence. Only two randomized clinical trials where adherence was not the primary outcome reported the effect of dosing changes, but focused, as did cross-sectional surveys, on patient preferences instead of cost-effectiveness. Observational studies and retrospective claims database reviews used different measures, definitions, and methodologies, making it difficult to summarize their results. Overall, the studies suggested that less frequent dosing leads to improved outcomes, although direct evidence of economic benefit was often lacking. CONCLUSIONS: Due to the lack of direct evidence, head-to-head direct comparisons of dosing regimens and long-term prospective studies are ideally needed to evaluate the cost-effectiveness of less frequent dosing that may improve outcomes through improved adherence or improved pharmacokinetic/pharmacodynamic effects.