Purpose: To compare the efficacy and side effects of betaxolol and timolol in treatment of primary open angle glaucoma or ocular hypertension.Patients and methods: This single-blind randomized cross-over clinical trial was conducted on 14 patients with primary open angle glaucoma or ocular hypertension. Each patient received timolol 0.5% and betaxolol 0.5% (Sina Darou) twice daily for two weeks in two phases. Before and between the two courses of treatment there was a wash-out period. At the end of the study the effect of these two drugs on intraocular pressure (IOP), mean arterial blood pressure, pulse rate, and basic tear secretion in addition to ocular symptoms were evaluated and statistically analyzed.Results: The study was performed on 14 patients with baseline IOP of 26.7±1.5 mmHg. After 2 weeks of treatment, timolol and betaxolol reduced IOP by 7.8±1.2 mmHg (29%) and 6.1±1.3 mmHg (23%), respectively (P<0.001) and the difference between the two groups was also significant (P<0.001). Mean arterial blood pressure was reduced with betaxolol and timolol by 4.7±7.1 mmHg (P<0.03), and 3.2±5.6 mmHg (P<0.05), respectively, but the difference between two groups was not significant. Pulse rate was reduced with timolol and betaxolol by 8 ±3.4 beats/min, and 6.5±5.6 beats/min, respectively (P<0.01), with no significant difference between two groups. Mean reduction in basic tear secretion with timolol and betaxolol was 0.8±2.1 mm/5min (P<0.2), and 0.5±1.9 mm/5min (p<0.3), respectively; intergroup comparison was also not significant. Patients in 85.7% of the betaxolol group and 35.7% of the timolol group complained of eye burning (P<0.01). Other symptoms were similar between two groups.Conclusion: Timolol is superior to betaxolol in treatment of early glaucoma or ocular hypertension, but both drugs should be used with caution in patients with cardiovascular compromise.