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To understand better the influence of retinal blood vessels (BVs) on the interindividual variation in the retinal nerve fiber layer (RNFL) thickness measured with optical coherence tomography (OCT).RNFL thickness profiles were measured by OCT in 16 control individuals and 16 patients. The patients had advanced glaucoma defined by abnormal disc appearance, abnormal visual fields, and a mean visual field deviation worse than −10 dB.In general, the OCT RNFL thickness profiles showed 4 local maxima, with the peak amplitudes in the superior and inferior regions occurring in the temporal (peripapillary) disc region. There was considerable variability among individuals in the location of these maxima. However, the 4 maxima typically fell on, or near, a major BV with the temporal and inferior peaks nearly always associated with the main temporal branches of the superior and inferior veins and arteries. In the patients' hemifields with severe loss (mean visual field deviation worse than −20 dB), the signals associated with the major BVs were in the order of 100 to 150 μm.The variation in the local peaks of the RNFL profiles of controls correlates well with the location of the main temporal branches of the superior and inferior veins and arteries. This correspondence is, in part, due to a direct BV contribution to the shape of the OCT RNFL and, in part, due to the fact that BVs develop along the densest regions of axons. Although the overall BV contribution was estimated to be relatively modest, roughly 13% of the total peripapillary RNFL thickness in controls, their contribution represents a substantial portion locally and increases in importance with disease progression.