BACKGROUND: Compliance or adherence to regimens and persistence over time are common concerns among doctors. The impact of oral once-daily [QD] or twice-daily [BID dosing regimen on adherence and persistence is unclear, and may potentially affect clinical and economic outcomes. OBJECTIVES: To investigate the effects of oral medication dosing frequency on adherence and persistence in a variety of chronic disease states that require long-term medication. METHODS: Relevant articles were identified through a systematic literature review from MEDLINE (2000-2011) using the terms adherence, oral, administration and dosage, QD, BID, once daily, twice daily, and treatment. Another search explored the secondary and tertiary references of relevant studies identified through the bibliographies of articles found in the primary search. RESULTS: Research articles (N=22) that met the search criteria comprised the following disease areas: HIV/AIDS (10 articles), diabetes (n=4), ulcerative colitis (n=2), depression/schizophrenia (n=2), hypertension/chronic heart failure/angina (n=4). 64% (14/22) of the studies observed improvement on adherence with the oral QD treatment in comparison to the BID regimen. Of those, 7 were for HIV drugs, 2 for hypertension/angina, 1 for ulcerative colitis, 3 for diabetes and 1 for depression. Articles evaluating drugs for the treatment of schizophrenia, HIV (3) and chronic heart failure found no impact on adherence. Persistence was measured in five of the studies, identified the following therapeutic areas: depression, diabetes and HIV. 80% (4/5) found significantly greater persistence among patients in the QD regimen vs. BID regimens. Consistently, significantly greater persistence was observed among patients with the QD versus BID regimens, except for one study in HIV, which showed no difference. CONCLUSIONS: The majority of studies evaluating adherence of oral QD vs. BID treatments for long-term drug treatments observed improvement of adherence and persistence with QD vs. BID treatment. The impact of oral drug dosing frequency can vary by therapeutic areas.