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Purpose To evaluate peripapillary vessel density and morphology in patients with diabetes mellitus (DM) without clinical signs of diabetic retinopathy (DR) and with mild, nonproliferative DR and to correlate with peripapillary nerve fiber layer (NFL) thickness. Methods One hundred seventeen eyes (34 healthy controls, 54 patients with DM without DR [noDR group] and 24 patients with mild DR [DR group]) were prospectively evaluated. All subjects underwent peripapillary and macular optical coherence tomography angiography (OCT-A). Peripapillary NFL thickness was also recorded. OCT-A slab of radial peripapillary plexus (RPC) and macular superficial capillary plexus (SCP) were analysed in order to calculate perfusion density (PD) and vessel density (VD). Further an image analysis of RPC slab was performed to identify number of branches (NoB) and total branches length (tBL). Results In peripapillary area there was a significant decrease in VD (P = 0.003), NoB (P < 0.001), and tBL (P < 0.001) in noDR group versus controls; PD values were not different among groups (P = 0.126); there was a significant decrease in average NFL thickness in DR versus controls (P = 0.008) and in the inferior quadrant in noDR group versus controls (P = 0.03); there was a significant correlation between OCT-A and NFL thickness values (ρ ranging from 0.19-0.57). In macular region PD and VD were decreased only in DR group (P < 0.05). Conclusions There are early changes in the peripapillary vessel morphology and VD of the RPC in patients with DM without DR that correlate to NFL thinning. Earlier changes in superficial vessel density are documented in the peripapillary than in the macular region. These data may confirm a coexistence of an early neuronal and microvascular damage in patients with DM without clinical signs of DR.