PurposeTo evaluate the proportion, predictors and outcomes of neovascular age-related macular degeneration (nAMD) patients treated with a high burden of vascular endothelial growth factor (VEGF) inhibitor injections (IVT) after two years in routine clinical practice. DesignRetrospective analysis of data from a prospectively designed observational outcomes registry, Fight Retinal Blindness! project, of patients treated in European centers. ParticipantsTreatment-naïve eyes (one eye per patient) starting VEGF inhibitors for nAMD from January 2017 to March 2020 with 24 months of follow-up. We analyzed three treatment burden groups defined by the mean interval of the three closest injections to the 24-month visit: (1) those with a high treatment burden had injection intervals ≤ 42 days, (2) those with a low treatment burden had injection intervals between 43 and 83 days and those with tolerable treatment burden had injection intervals between 84 and 365 days. MethodsMultinomial regression was used to evaluate baseline risk predictors of patients requiring a high treatment burden. Main Outcome MeasuresThe proportion of patients that experienced a high treatment burden at 2 years and its predictors. ResultsWe identified 2,038 eligible patients completing 2 years of treatment (2038/3943 patients [60%]) with a median (Q1, Q3) of 13 (10, 17) injections. The proportion of patients with a high treatment burden was 25% (516 patients) at 2 years. Younger patients (Odds ratio (OR), 0.97; 95%CI, 0.96-0.99; P<0.01) were more likely to have high treatment burden, while eyes with type 3 CNV at baseline were significantly less likely (OR, 0.26; 95%CI, 0.13-0.52; P<0.01). Regarding type of fluid, patients with subretinal fluid only at baseline (OR, 3.85; 95%CI, 1.34-11.01; P=0.01) and persistent active intraretinal (OR, 1.56; 95%CI, 1.18-2.06; P<0.01) or subretinal fluid only (OR, 2.21; 95%CI, 1.52-3.21; P<0.01) after the loading phase had a higher risk of high treatment burden at 2 years. ConclusionsHigh treatment burden is common issue in routine clinical practice in Europe, with a quarter of patients requiring injections of conventional VEGF inhibitors every 6 weeks at 2 years and 40 percent discontinuing treatment within 2 years.