Introduction: The aim of this study is to assess and compare the long-term clinical efficacy of anti-VEGF drugs using the Imaculaweb registry. Methods: In this observational study based on the Imaculaweb registry, outcome measures were the number of injections, the change in mean visual acuity (VA) and central macular thickness (CMT), and the time between diagnosis and the first injection. Results: In total, 126 eyes of 109 patients were included in the study. The mean VA was 49.4 ± 21.4, 54.1 ± 22.2, 51.6 ± 24.9, and 48.3 ± 25.7 letters at baseline and at the 1-, 2-, and 3-year follow-ups, respectively. Significant VA increases (p = 0.0002 for the first year and p = 0.045 for the second year) were documented at years 1 and 2 but not at year 3 (p = 0.8). The mean number of injections was 5.2, 2.6, and 2.3 at the 1-, 2-, and 3-year follow-ups, respectively. In the first year, 30% of the patients received at least 7 injections, while only 6.4% received <3 injections. CMT decreased significantly during the overall follow-up period, and intra- and subretinal fluid decreased (p < 0.0001). Conclusion: Imaculaweb turned out to be an effective tool to collect and share clinical data as well as to monitor patient outcome.