PURPOSE. To investigate the relationship between enlargement of the foveal avascular zone (FAZ) and structural changes on spectral-domain optical coherence tomography (SD-OCT) in patients with ischemic diabetic macular edema (DME). METHODS. This was a retrospective, cross-sectional study including 35 eyes of 33 patients with ischemic DME as determined by irregular margins of the FAZ in fluorescein angiography. We measured the best-corrected visual acuity (BCVA), central subfield thickness (CST), subfield volume, subfoveal choroidal thickness, length of the photoreceptor outer segment (PR-OS), and the lateral extent of inner segment-outer segment (IS-OS) disruption on SD-OCT images, as well as the FAZ to optic nerve head (FAZ/ONH) area ratio by using the ImageJ program. RESULTS. The mean FAZ/ONH area ratio was 0.28 +/- 0.15. The FAZ/ONH area ratio was positively correlated with the logarithm of the minimum angle of resolution (LogMAR) BCVA (P = 0.001, r = 0.529). The mean CST was 391 +/- 110 mu m, and the subfield volume was 0.31 +/- 0.09 mm(3). The mean length of the PR-OS and the horizontal and vertical extent of IS-OS disruption were 40 +/- 8 mu m, 169 +/- 294 mu m, and 114 +/- 170 mu m, respectively. The mean length of the PR-OS and the horizontal and vertical extent of IS-OS disruption were significantly correlated with FAZ/ONH area ratio (P = 0.020, P = 0.001, and P = 0.049, respectively). The horizontal and vertical extent of IS-OS disruption showed a positive correlation with LogMAR BCVA (P = 0.027 and P = 0.049, respectively). CONCLUSIONS. Foveal ischemia in DME appears to cause PR-OS shortening and IS-OS disruption resulting in outer retinal layer atrophic changes and subsequent visual loss. (Invest Ophthalmol Vis Sci. 2013;54:1080-1085) DOI:10.1167/iovs.12-10503