Purpose: To characterize retinal pigment epithelial (RPE) cell loss as evidenced by autofluorescence imaging in patients with neovascular age-related macular degeneration (AMD). Design: Retrospective cohort study. Participants: There were 162 eyes of 116 consecutive patients with neovascular AMD examined in a retinal practice. Methods: Each patient underwent a complete examination including autofluorescence imaging. Areas of confluent absence of autofluorescence signal of at least 0.5 mm in greatest linear diameter were measured within the macular area. Patient demographic and examination data were evaluated in relation to the autofluorescence data. Main Outcome Measures: Prevalence and progression of confluent areas of absent autofluorescence and the relationship these areas had with visual acuity. Results: The mean age of the patients was 82.9 years, and the mean visual acuity was 20/71 (logarithm minimum angle of resolution [logMAR], 0.55). Confluent loss of autofluorescence was seen in 58.6% of eyes at baseline, and the median area of absent autofluorescence among those was 1.57 mm2 (interquartile range [IQR], 0.62-4.32 mm2). Using generalized estimation equation modeling, the significant predictors for area of confluent absent autofluorescence at baseline were duration of disease and any previous treatment with photodynamic therapy. The significant predictor of baseline visual acuity was baseline area of confluent absent autofluorescence. Follow-up was available for 124 (76.5%) eyes, with a mean follow-up of 2.9 years. By then, the mean visual acuity was 20/90 (logMAR, 0.65), and 79% of eyes had confluent areas of absent autofluorescence, the large majority of which affected the central macula. The median area of absent autofluorescence was 3.61 mm2 (IQR, 1.16-7.11 mm2). The best predictor of final visual acuity was the area of absent autofluorescence at the final follow-up. Conclusions: Confluent absence of autofluorescence, a measure signifying RPE loss, was a significant predictor of visual acuity both at baseline and at final follow-up. This is the first study to document the prevalence, rate of progression, and factors associated with measures of confluent RPE loss in patients with neovascular AMD. Application of strategies to limit RPE cell loss may prove useful in eyes with neovascular AMD. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.