BACKGROUND: The potential value of low-voltage area (LVA) ablation for persistent atrial fibrillation (AF) has been suggested. However, its efficacy determinants remain unclear. We investigated the impact of diabetes on the outcomes of LVA ablation in patients with persistent AF. METHODS: This post hoc subanalysis of the multicenter randomized controlled trial SUPPRESS-AF (Efficacy and Safety of Low-Voltage-Guided Ablation for Recurrence Prevention Compared With Pulmonary Vein Isolation Alone in Patients With Persistent Atrial Fibrillation) included patients with persistent AF undergoing initial ablation. Following pulmonary vein isolation (PVI), patients with LVAs were randomized to PVI+LVA-ablation or PVI alone. We compared recurrence-free survival between patients with and without diabetes. The primary end point was freedom from AF/atrial tachycardia recurrence. RESULTS: Of 1347 patients with persistent AF, 343 (25.5%) had left atrial LVAs. The nondiabetic group comprised 264 patients (136 and 128 in the PVI-alone and PVI+LVA-ablation arms, respectively), and the diabetic group comprised 77 patients (35 and 42 in each arm, respectively). No significant difference was observed in LVA extent between the groups. Overall recurrence rates were also similar (44% versus 42%; P=0.658). In the nondiabetic group, the PVI+LVA-ablation arm showed significantly lower recurrence rates compared with the PVI-alone arm (35% versus 49%; P=0.018). Conversely, patients with diabetes exhibited higher recurrence rates in the PVI+LVA-ablation arm compared with those in the PVI-alone arm (48% versus 40%; P=0.290). A significant interaction was observed between diabetes status and LVA ablation efficacy (P for interaction=0.041). CONCLUSIONS: In this exploratory post hoc analysis, LVA ablation may benefit patients without diabetes, whereas no clear benefit, and a possible signal of futility, was observed in patients with diabetes.