Purpose <p>To assess the macular vascular effects of prolonged use of latanoprost compared to the dorzolamide-timolol fixed combination in patients with very early-stage glaucoma, where glaucoma-specific damage has been minimized.</p> Methods <p>The retinal vascular effects of latanoprost versus the dorzolamide-timolol fixed combination were evaluated using Optical Coherence Tomography Angiography (OCT-A) in a case–control study design. A total of 71 eyes from 71 individuals were included in the study: 28 eyes receiving latanoprost (Group 1), 20 eyes receiving the dorzolamide-timolol combination (Group 2), and 23 eyes from healthy individuals (Group 3). Superficial, deep, and radial peripapillary capillary plexus vascular density (SCP-vd, DCP-vd, RPCP-vd) and foveal avascular zone (FAZ) measurements were taken with OCT-A. The comparative analysis between groups was performed with SPSS V.26.</p> Results <p>Across the groups (from 1 to 3), whole image vascular density (vd) measurements were as follows: SCP-vd: 45.86 ± 3.99, 44.58 ± 4.58, 48.35 ± 4.04; DCP-vd: 44.86 ± 5.75, 44.02 ± 6.87, 49.74 ± 4.84; and RPCP-vd: 46.97 ± 3.81, 47.07 ± 5.49, 49.90 ± 2.43. All these measurements were significantly decreased in both glaucoma groups (groups 1 and 2) compared to healthy subjects (group 3). In subgroup analyses of the macular region, including the fovea, parafovea, and perifovea, vd measurements were decreased in all areas except the fovea in glaucoma patients. However, no statistically significant differences were found between the latanoprost and dorzolamide-timolol groups regarding retinal vascular structure. In FAZ measurements, no significant differences were found in any anatomical location among the three groups.</p> Conclusion <p>This study demonstrates that latanoprost, the first prostaglandin analog known for its edema-inducing effect on the macula, does not have a long-term impact on macular vascularity. However, this result should be supported with longer and larger studies.</p>