In a 4-year, double-masked, parallel, multicenter study comparing the efficacy and safety of levobunolol and timolol, 391 patients with open-angle glaucoma or ocular hypertension were randomly assigned to receive masked 0.5% or 1% levobunolol, or 0.5% timolol, twice daily. Mean decreases in intraocular pressure (IOP) over 4 years of therapy were 7.1, 7.2, and 7.0 mmHg for 0.5% levobunolol, 1% levobunolol, or 0.5% timolol, respectively. Little attenuation of ocular hypotensive efficacy occurred. The 4-year efficacy failure rate for the three groups, which did not differ from each other, was approximately 30%. Adverse experiences requiring cessation of therapy occurred in an additional 10% of patients. The vast majority of efficacy failures (79/95) and of adverse events (33/37) requiring removal from the study occurred during the first 2 years. Overall mean decreases in heart rate for the 4 years ranged from 3 to 6 beats per minute for all treatment groups; overall mean decreases in systolic and diastolic blood pressure ranged between 1 and 2 mmHg. The authors concluded that levobunolol is relatively effective and relatively safe for the long-term (4-year) treatment of elevated IOP.