PURPOSE: To evaluate the efficacy and safety of brimonidine compared with dorzolamide given three times daily as monotherapy in patients with primary open-angle glaucoma or ocular hypertension. METHODS: In a double-masked, multicenter, crossover comparison in 40 patients, qualified patients were washed out from their previous medication and randomized to dorzolamide 2% or brimonidine 0.2% for the first 6-week treatment period. Patients then were washed out for 2 weeks and started on the opposite medication for the second 6-week period. RESULTS: Baseline intraocular pressure for all 40 subjects (76 eyes) was 24.1 ± 2.0 mm Hg. This study found that the 8:00 am trough intraocular pressure after 6 weeks of therapy for dorzolamide was 20.7 ± 3.1 mm Hg and for brimonidine 20.8 ± 3.2 mm Hg ( P = .99). The peak intraocular pressure (2 hours after dosing) for dorzolamide was 18.6 ± 3.4 mm Hg and for brimonidine 17.8 ± 2.7 mm Hg ( P = .10 ). Dorzolamide caused more stinging upon instillation ( P < .01) and brimonidine more itching ( P = .01). No statistical differences existed between groups for systemic adverse events. Six patients, all on brimonidine, were discontinued from a treatment period early. Of these, two were discontinued for inadequate pressure control, two with dizziness and fatigue, one with ocular pain, and one for lifestyle reasons ( P = .07). CONCLUSIONS: This study found similar efficacy and safety between monotherapy treatment with dorzolamide or brimonidine when each was given three times daily to patients with ocular hypertension or primary open-angle glaucoma.