OBJECTIVE: To compare outcomes of intravitreal therapy from an observational study cohort with those of participants receiving treatment in the Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab (MARINA) for the treatment of neovascular age-related macular degeneration (wet AMD). DESIGN: Database observational study. Participants in the observational cohort were chosen to match demographic features and entry criteria of the treatment group from MARINA. Outcomes over 12 months were compared. PARTICIPANTS: Eight hundred twenty-one anti-vascular endothelial growth factor (anti-VEGF)-naïve eyes treated with ranibizumab with 12 months or more of follow-up were included in the total Fight Retinal Blindness! (FRB-All) cohort, whereas a subset of this cohort of 401 eyes who were matched to the MARINA treatment group were included as the FRB-MARINA cohort. INTERVENTION: Intravitreal ranibizumab therapy of 0.5 mg for wet AMD. METHODS: Visual acuity (VA) in logarithm of the minimum angle of resolution (logMAR) letters and treatments given were recorded continuously and anonymously in an electronic database for 12 months. Locally weighted scatterplot smoothing (LOESS) regression was used to plot change in visual acuity data over the course of 12 months for both the FRB-All cohort and the FRB-MARINA cohort, whereas results from the MARINA trial were taken from the published study report. MAIN OUTCOME MEASURES: Change in VA in logMAR letters over 12 months, treatment, and visit intensity. RESULTS: Mean visual acuity improvement after 12 months in FRB-MARINA (+5.5 letters) was similar to that of the 0.5-mg group from MARINA (+7.2 letters). Improvement in FRB-ALL was slightly less (+4.9 letters). Mean treatment effect compared with the MARINA control group was similar for the MARINA treated group (+17.6 letters) and the FRB-MARINA cohort (+15.9 letters). A mean of 7.3 injections in 12 months was received by the observational cohorts. CONCLUSIONS: Similarity of mean VA improvement in the matched observational cohort with that of the phase 3 clinical trial suggests that these results can be achieved in real-world clinical practice with a modified treatment regimen. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.