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Purpose To explore the association between early response of different lesions and the number of anti-vascular endothelial growth factor (anti-VEGF) injections in neovascular age-related macular degeneration (nAMD).Methods This prospective study included treatment-naïve nAMD eyes with a 2-year follow-up period. Volumetric changes of multiple lesions during the loading phase were documented, including subretinal fluid (SRF), intraretinal fluid (IRF), vascular subretinal hyper-reflective material (vSHRM) and avascular subretinal hyper-reflective material, fibrovascular pigment epithelial detachment and serous pigment epithelial detachment (sPED) and total lesion. Imaging biomarkers associated with treatment frequency were analysed for 1-year and 2-year periods.Results A total of 92 eyes (92 patients) were included, with a mean age of 65.77±7.28 years. During the loading phase, all lesions except vSHRM showed significant temporal changes (p<0.05). Multivariate regression revealed that greater SRF changes at month 3 and IRF changes at month 1 were associated with increased injection frequency for both 1-year (β=0.353 and 0.360, p=0.025 and 0.022) and 2-year periods (β=0.336 and 0.293, p=0.004 and 0.026). Conversely, greater changes in vSHRM and sPED at month 2 were associated with fewer first-year injections (β=−0.307 and −0.697, p=0.023 and 0.022), while sPED changes at months 2 and 3 correlated with reduced 2-year requirements (β=−0.845 and −0.297, p=0.005 and 0.031).Conclusion Enhanced absorption of SRF and IRF during early treatment was associated with increased injection frequency, while greater absorption of vSHRM and sPED correlated with reduced treatment requirements.Trial registration number ChiCTR2200063428.