Glaucoma is a chronic ophthalmic disease and untreated leads to progressive loss of vision. OBJECTIVES: The purpose of this study was to perform a cost-effectiveness analysis of first-line monotherapy medications for the treatment of glaucoma. METHODS: This study was a cost-effectiveness analysis of latanoprost, brimonidine and beta-blockers for treatment of glaucoma. Data for the study came from a VA medical center. Patients were eligible if they had a prescription for latanoprost, brimonidine or beta-blockers as monotherapy for glaucoma. The outcomes of interest were change and percent change in intraocular pressure (IOP). The perspective of the analysis was from that of a VA medical center and included direct medical costs. RESULTS: A total of 318 eyes were evaluated, 78 receiving beta blockers, 34 receiving brimonidine, and 206 receiving latanoprost. The majority of patients were white males and the mean age was 73 years. Patients receiving latanoprost had a mean(SD) IOP reduction of 7.59(4.6) mmHg compared to 6.8(5.0) mmHg for beta-blockers (p = 0.18), and there was no significant difference was observed between the mean for brimonidine (7.1(4.7) mmHg) and beta-blockers (p = 0.76). The mean percent change in IOP was identical for latanoprost and brimonidine (29.6%), but only 24.8% for those receiving beta-blockers. Average (SD) daily cost was $0.05(0.09) for beta-blockers, $0.29(0.39) for brimonidine, and $0.30(0.42) for latanoprost (p <0.001). However, the most cost-effective agent was brimonidine, with a daily cost of $7.15 for each percent reduction in IOP. Latanoprost demonstrated a daily cost per percent IOP reduction of US$7.58. Both brimonidine and latanoprost were more cost-effective than the beta-blockers with a cost-effectiveness ratio of US$8.42. The incremental cost-effectiveness of using brimonidine or latanoprost compared to beta-blockers was $3.23 and $5.05, respectively. CONCLUSIONS: The results suggest that despite a much lower cost, beta-blockers are not more cost-effective than brimonidine or latanoprost.