Background: Glaucoma is a chronic, progressive optic neuropathy which leads to optic nerve damage and loss of visual function. Elevated intraocular pressure (IOP) is the most important and only modifiable risk factor. Hence, the goal of glaucoma therapy is to lower IOP, and ocular hypotensive agents have the potential to prevent optic nerve damage and preserve vision. Aims and Objectives: Aims and objectives of the study are to compare the efficacy and safety of timolol 0.5% versus latanoprost 0.005% in the treatment of primary open-angle glaucoma (POAG). Materials and Methods: A total of 60 newly diagnosed patients of POAG who fulfilled the inclusion/exclusion criteria were enrolled and randomized into two groups of 30 each to receive timolol 0.5% twice daily and latanoprost 0.005% once daily in the evening. IOP was recorded at baseline and each follow-up visit. The patients were followed every 4 weeks for 12 weeks. Adverse effects, if any, were also recorded at each visit. Results: At 12 weeks both timolol and latanoprost effectively reduced IOP, but the reduction was significantly greater (P < 0.0001) with latanoprost (7.97 ± 1.27 mmHg, 31.25%) compared with timolol (6.77 ± 1.48 mmHg, 25.9%). More number of eyes (χ 2 = 4.6, df = 1, P = 0.032) treated with latanoprost (46, 76.6%) achieved a specific target IOP as compared to those treated with timolol (35, 58.3%). Both the study medications were well tolerated. Conclusion: Latanoprost was found to be more potent and efficacious in reducing IOP with good tolerability in patients with POAG.