PURPOSE: To investigate the incidence, characteristics, and baseline predictors of poor visual outcomes in eyes with neovascular age-related macular degeneration (nAMD) receiving intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents in daily clinical practice. DESIGN: Observational study. PARTICIPANTS: Treatment-naive eyes starting anti-VEGF therapy for nAMD between 2007 and 2012 tracked in the Fight Retinal Blindness! registry. Eyes had sustained ≥15 letters of loss from baseline without recovery of visual acuity (VA) at final end point. A subgroup analysis included eyes that sustained ≥30 letters of loss. Controls had not sustained ≥15 letters of loss. METHODS: Kaplan-Meier curves estimated time to first development of loss of ≥15 letters. Cox proportional hazards models evaluated predictors of loss of ≥15 letters. MAIN OUTCOME MEASURES: The proportion of eyes with sustained VA loss within 5 years, the time to development of sustained VA loss, and baseline predictors of sustained VA loss. RESULTS: There were 1760 eyes in total and 856 eyes that completed 5 years follow-up. The proportion of eyes with sustained VA loss of ≥15 letters at 5 years was 22.9% (95% confidence interval [CI], 20.7%-25.1%) and VA loss of ≥30 letters was 10.8% (95% CI, 9.1%-12.5%). Factors independently associated with higher incidence of sustained ≥15-letter loss included age >80 years (odds ratio [OR], 1.33 for patients >80 years vs. ≤80 years; 95% CI, 1.05-1.69; P = 0.02), fewer injections (OR, 0.97 per injection; 95% CI, 0.96-0.98; P = 0.0005), and more visits at which the choroidal neovascularization was graded as active (OR, 1.97 for eyes in upper quartile of active visits vs. eyes in lowest quartile of active visits; 95% CI, 1.39-2.79; P = 0.0001). Baseline VA ≥70 letters was associated with reduced risk of sustained ≥30-letter loss (OR, 0.61; 95% CI, 0.38-0.98; P = 0.04). Baseline angiographic lesion criteria were not significantly associated with sustained VA loss. CONCLUSIONS: Twenty-three percent of eyes with nAMD developed sustained VA loss of ≥15 letters over 5 years of anti-VEGF therapy. Baseline predictors of poor outcomes provide more accurate assessment of the potential benefit from anti-VEGF therapy.