PURPOSE: To classify retinal nonperfusion regions (NPRs) in patients with diabetic macular edema (DME) and assess the relationship with severity of DME. DESIGN: Prospective, observational case series. METHODS: Forty eyes of 29 patients with treatment-naive center-involved macular edema secondary to diabetes mellitus were included (The DAVE study, NCT01552408) in this analysis. Ultra-widefield fluorescein angiography (UWF FA) images were transmitted to the Doheny Image Reading Center, where they were corrected using stereographic projection to adjust for peripheral distortion. Two independent, certified graders manually evaluated the NPR and classified the nonperfusion as being associated with leakage or without leakage. The size of these 2 subtypes of NPR were computed in mm 2 and assessed across the entire retina and within 3 concentric retinal zones. The relationship between subtype of NPR and the severity of DME was assessed. RESULTS: In 40 eyes with treatment-naive DME, visual acuity was significantly correlated with central macular thickness (CMT) and macular volume (MV). The NPR with leakage was positively correlated with CMT (R = 0.408, P = .009) and MV (R = 0.399, P = .011), whereas the NPR without leakage was negatively correlated with CMT (R = - 0.468, P = .002) and MV (R = - 0.473, P = .002). The NPR with leakage in the posterior region was significantly greater compared to the mid-periphery and the far periphery (P < .001), whereas the NPR without leakage was significantly greater in the mid-periphery compared with the far periphery or the posterior region (P = .001). CONCLUSION: In patients with DME, the severity of DME appears to be positively correlated with NPR with leakage but negatively correlated with NPR without leakage. These findings may have implications for the pathophysiology of DME and the design of protocols for targeted laser in these eyes. (C) 2019 Elsevier Inc. All rights reserved.