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Purpose: To investigate the impact of blood pressure (BP) on rates of retinal nerve fiber layer (RNFL) thinning in glaucomatous eyes with focal ischemic (FI) versus generalized enlargement (GE) optic disc phenotypes., Design: Prospective cohort study., Participants: The study included 122 eyes from 101 patients diagnosed with primary open-angle glaucoma. Eyes were classified as FI (n=31, 25%) or GE (n=91, 75%) based on masked grading of stereophotographs at baseline., Methods: Subjects underwent comprehensive ophthalmic examinations, including intraocular pressure (IOP) measurement and spectral-domain optical coherence tomography (SD-OCT) scans, every 6 months for an overall mean follow-up of 4.2 years ± 1.5 years. Brachial artery BP was measured concurrently, and mean arterial pressure (MAP), systolic arterial pressure (SAP), and diastolic arterial pressure (DAP) were calculated. Rates of global RNFL thickness change over time were assessed using linear mixed models, evaluating the impact of BP parameters in each optic disc phenotype, adjusting for IOP and other confounders. Interaction terms were used to test for differences in the effects of BP and IOP between the FI and GE phenotypes., Main Outcome Measures: Effect of MAP, SAP and DAP on rates of RNFL loss over time in FI and GE optic disc phenotypes., Results: In the adjusted FI group models, each 10-mmHg decrease in MAP, SAP, and DAP was associated with -0.397 μm/year (p=0.006), -0.211 μm/year (p=0.029), and -0.471 μm/year (p=0.005) faster RNFL thinning, respectively. In contrast, BP parameters were not significantly associated with RNFL loss in the GE group. In the multivariable model with interaction terms, the interaction between DAP and phenotype was statistically significant (p=0.019), indicating the FI phenotype exhibited greater sensitivity to lower diastolic pressure compared to GE eyes. In contrast, interaction terms between IOP and optic disc phenotype were not significant in any of the models, suggesting a similar effect of IOP in both phenotypes., Conclusion: Lower systemic BP levels were associated with faster RNFL thinning in the FI optic disc phenotype, but not in the GE phenotype. These findings highlight the importance of considering both IOP and systemic BP when managing patients with the FI optic disc phenotype., (Copyright © 2025. Published by Elsevier Inc.)