PURPOSE To compare the tolerance and peak intraocular pressure (IOP)-lowering efficacy of brimonidine and latanoprost as adjunctive therapy in patients with ocular hypertension or glaucoma uncontrolled on beta-blockers. DESIGN A prospective, multicenter, double-masked, parallel-design clinical trial. PARTICIPANTS One hundred fifteen patients with IOP inadequately controlled on topical beta-blocker monotherapy. METHODS Patients were randomly assigned to receive brimonidine, 0.2%, twice a day or latanoprost, 0.005%, every day as adjunctive therapy for 3 months. After 1 month of adjunctive treatment, patients who failed to meet a target 15% reduction in IOP at peak drug effect were crossed over to the other study medication. The target sample size of 51/group gave a power of 0.80 to detect a difference of 1 mmHg in mean IOP lowering between groups. MAIN OUTCOME MEASURES The primary outcome variables were reduction in IOP from baseline at peak drug effect, response rate, and quality of life as measured using the Glaucoma Disability Index. RESULTS Mean beta-blocker-treated baseline IOP was comparable between treatment groups (approximately 21.3 mm Hg). After 1 month of adjunctive therapy, brimonidine and latanoprost provided comparable IOP lowering (4.88 mmHg [22.8%] with brimonidine and 5.01 mmHg [23.5%] with latanoprost, P = 0.798). Response rates were similar in both groups, with 44 of 54 brimonidine patients and 43 of 53 latanoprost patients achieving the minimum target 15% IOP reduction at peak drug effect at month 1 (P = 0.963). Among patients who were successful at month 1 and continued on the initial study medication, mean IOP reductions were 4.55 mmHg with brimonidine and 5.49 mmHg with latanoprost (P = 0.149) at month 3. There was no significant difference in the ability of brimonidine and latanoprost to maintain at least a 15% additional reduction in IOP for 3 months (28 of 38 patients on brimonidine vs. 30 of 36 patients on latanoprost achieved > or =15% IOP reduction at month 3; P = 0.314). Patients in the latanoprost group were more likely to report negative quality-of-life variables than patients in the brimonidine group. Significantly more latanoprost patients reported watery or teary eyes (34 of 53, 64.2% vs. 23 of 54, 42.6% with brimonidine; P = 0.025) and hands and feet that became cold easily (24 of 53, 45.3% vs. 12 of 54, 22.2% with brimonidine; P = 0.012). CONCLUSIONS As adjunct therapy with beta-blockers, brimonidine twice daily and latanoprost every day were comparable in lowering IOP at peak effect, but brimonidine was better tolerated, with fewer reports of adverse quality-of-life effects.