OBJECTIVES: To compare patient adherence with chronic-use prescription medications between once- (QD) and twice-daily (BID) dosing. METHODS: Using a large claims database (MarketScan), prescription medications were defined as QD if ≥80% of claims showed a quantity/day=1 and were defined as BID if ≥80% of claims had a quantity/day=2.  Data for patients (18 years or older) with the first claim in 2007 were selected for analysis and were further limited to 4 classes of medications frequently used by cardiovascular patients:  antiplatelet, general cardiac, antihyperlipidemic, or antidiabetic medications.  Adherence was measured by medication possession ratio (MPR) defined as the number of days of medication supplied (between the first prescription fill date and 365 days following)/365 days.  A linear model (generalized estimating equation) accounting for within-patient correlations in patients using multiple medications was used to model the MPR.  The model was stratified on medication class and adjusted for baseline confounding variables (gender, age, Charlson Comorbidity Index). RESULTS: A total of 1,077,936 patients were included, and the number of patient-medication combinations was 1,440,917 (QD:  1,384,565 and BID:  56,352).  The mean MPR for BID compared to QD was -5% overall and -28% for antiplatelet agents, -19% for antihyperlipidemic agents, -7% for antidiabetic agents, and 3% for cardiac agents (p<0.01 for all comparisons). CONCLUSIONS: This unique, recent, claims analysis, which investigated multiple therapeutic classes of medications in a large database, generally found lower adherence in BID dosing in medications frequently used by cardiovascular patients; however, a wide range in the MPR differences between QD and BID dosing was observed between the therapeutic classes.  Further research is needed to investigate the relationship between dosing complexity and therapeutic class of medications and subsequent patient adherence.