This report investigated patients who lost more than two lines of vision despite periodic injections of aflibercept and explored the factors associated with vision loss. One hundred and ninety-six eyes were included in this study over a two year period. Typical age-related macular degeneration (AMD) accounted for 101 eyes, polypoidal choroidal vasculopathy (PCVP) for 80 eyes, and 15 had retinal angiomatous proliferation (RAP). Among 196 patients, 168 (85.7%) were followed for one year. The mean number of injections was 6.56 (95% confidential interval: 6.39–6.72). Among the study eyes, 16 (8.2%) experienced more than two lines of decline of vision, which included 10 eyes with typical AMD (9.9% of eyes with typical AMD), four eyes with PCVP (5.0% of eyes with PCVP), and two eyes with RAP (13.3% of eyes with RAP). The presumed cause for visual decline was an increase / development of subretinal haemorrhage (four eyes, 25.0%), development of an retinal pigment epithelium (RPE) tear (three eyes, 18.8%), formation of a fibrotic scar (three eyes, 18.8%), an increase of cystoid macular oedema (CME; two eyes, 12.5%), an accumulation of fibrin (one eye, 6.3%), and development of geographic atrophy (GA; one eye, 6.3%). Patients with vision loss were older, had a larger greatest linear dimension and a higher pigment epithelial detachment (PED), had a disrupted external limiting membrane (ELM), and had more frequent subretinal haemorrhage. In logistic regression analysis, the height of the PED and disrupted ELM were identified as factors that contributed to vision loss.