Metoprolol is a widely used anti-ischemic drug with a relatively short half-life. To improve patient' compliance and to provide 24-hour coverage, its once daily ORally OSmotic (OROS) formulation was developed. In this multicenter double-blind study, the anti-ischemic effects of metoprolol OROS given once daily at doses of 190 and 285 mg were compared to the regular metoprolol formulation of 100 mg 2 or 3 times daily. Sixty-five patients with stable coronary artery disease, positive exercise tests, and ischemic episodes during daily activity as recorded by ambulatory electrocardiographic monitoring (AEM) were included. In the OROS group, 23 patients completed all 3 treatment periods. In these patients, the number of myocardial ischemic episodes decreased from 239 on placebo to 128 during the 190 mg/day dose (p < 0.0001) and to 86 during the 285 mg/day treatment period (p < 0.0001). In the metoprolol group, there were 204 episodes at baseline and 142 and 140 during the 100 mg 2 or 3 times daily treatment periods (p < 0.0001 for both). During exercise testing, time to 1-mm ST depression increased significantly in the OROS group from 6.3 minutes at baseline to 7.1 and 9.6 minutes during 190- and 285-mg treatment periods. In the metoprolol group, it increased from 5.8 to 7.2 and 8.2 minutes, respectively. Both formulations of metoprolol were well tolerated. The OROS formulation was highly effective in suppressing daily and exercise-induced ischemia and exerted its effect throughout the 24-hour period.