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Introduction: To examine the association between retinal thickness (RT) fluctuations and best-corrected visual acuity (BCVA) in eyes with neovascular AMD, macular edema secondary to RVO, and DME treated with anti-VEGF therapy. Methods: A systematic search of Ovid MEDLINE, EMBASE, and the Cochrane Library was performed from January 2006 to March 2024. Studies comparing visual or anatomic outcomes of patients treated with anti-VEGF therapy, stratified by magnitudes of RT fluctuation, were included. ROBINS-I and Cochrane RoB 2 tools were used to assess risk of bias, and certainty of evidence was evaluated with GRADE criteria. Meta-analysis was performed with a random effects model. Primary outcomes were final BCVA and change in BCVA relative to baseline. Results: 15725 articles were screened; 15 studies were identified in the systematic review and 5 studies were included in the meta-analysis. Final ETDRS VA was significantly worse in eyes with the highest level of RT fluctuation (weighted mean difference (WMD) = 7.86 letters; 95% CI, 4.97, 10.74; p < 0.00001; I² = 81%; 3136 eyes). RT at last observation was significantly greater in eyes with high RT fluctuations (WMD = –27.35 μm; 95% CI, –0.04, 54.75; p = 0.05; I2 = 88%; 962 eyes). Conclusions: Final visual outcome is associated with magnitude of RT fluctuation over the course of therapy. It is unclear whether minimizing RT fluctuations would help to optimize visual outcomes in patients treated with anti-VEGF therapy. These findings are limited by a small set of studies, risk of bias, and considerable heterogeneity.

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