Objective: To study the relationship between spectral domain optical coherence tomography (SD-OCT) findings and fluorescein angiography (FA) patterns in patients with diabetic macular edema (DME). Design: Retrospective, observational, cross-sectional study. Participants: We included 59 eyes from 59 patients with DME that had SD-OCT/scanning laser ophthalmoscope (SLO) and FA performed on the same day. Eyes with macular edema owing to other ocular diseases were excluded. Methods: The relationship between SD-OCT and FA findings was evaluated by superimposing and aligning the SLO images onto the FA photos. The SLO image of the OPKO/OTI Spectral OCT/SLO (OPKO-OTI, Miami, FL) corresponds with the exact origin and orientation of the SD-OCT scan, which was then correlated with the FA image. Foveal and extrafoveal regions were studied separately. Leakage on FA and pathologic changes on OCT were graded by using standard photographs. Pathologic changes studied in the OCT images included edema and cystic spaces in the inner and outer retina, loss of retinal layers, and foveal cysts. Main Outcome Measures: Correlation between SD-OCT changes and corresponding FA patterns. Results: The outer retina was the predominant location of fluid in DME. The severity of the outer retinal edema on OCT was positively correlated with the severity of leakage on FA (r = 0.735; P<0.001). Cystic changes in the inner and outer retina were also correlated with the severity of fluorescein leakage (r = 0.507 and P<0.001; r = 0.561 and P<0.001, respectively). Loss of inner retinal layers on OCT was highly correlated with capillary nonperfusion on FA (r = 0.953; P<0.001). Large foveal cysts on SD-OCT corresponded to cystoid leakage patterns on FA. Conclusions: Pathologic changes on SD-OCT correlated well with FA findings. Loss of inner retinal layers was specifically correlated with capillary nonperfusion and severe ischemia. Judgment of whether management of DME based on fine retinal structural changes influences clinical outcomes must be reserved pending further investigation with prospective trials. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.