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Purpose: Intravitreal injection (IVI) of anti-vascular endothelial growth factor (VEGF) is the standard of care for neovascular age-related macular degeneration (nAMD). However, a small subgroup of patients still experience severe visual impairment, which may be related to the number of IVI administered., Methods: This retrospective observational study analyzed data from patients with sudden severe visual decline (≥15 Early Treatment Diabetic Retinopathy Study [ETDRS] letters loss between two consecutive IVIs) during anti-VEGF treatment for nAMD. Best-corrected visual acuity examination, optical coherence tomography (OCT), and OCT angiography (OCTA) were performed before every IVI and central macular thickness (CMT) and drug injected were collected., Results: 1,019 eyes received anti-VEGF IVI for nAMD from December 2017 to March 2021. Severe VA loss occurred in 15.1% after a median of 6 (range 1-38) IVI. Ranibizumab was injected in 52.8% and aflibercept in 31.9% of cases. Functional recovery after 3 months was significant, without further improvement at 6 months. Visual prognosis relative to the percentage of CMT change showed better visual outcome in eyes with no substantial change in CMT compared with an increase of >20% or a decrease of >5%., Conclusion: In this first real-life study exploring severe VA loss during anti-VEGF treatment in patients with nAMD, it was found that it was not unusual for a ≥15 ETDRS letters loss to occur between two consecutive IVIs, often within 9 months of diagnosis and 2 months after the last IVI. Close follow-up and a proactive regimen should be preferred, at least in the first year.