Purpose <p>The incidence and timing of first lesion reactivation following initial loading injections of faricimab for neovascular age-related macular degeneration (AMD) were assessed, and factors related to lesion reactivation were analyzed.</p> Methods <p>This retrospective study included patients with treatment-naive neovascular AMD who underwent either three or four monthly loading injections of faricimab and completed 12 months of follow-up. The incidence and timing of the first lesion reactivation following the initial loading phase were analyzed and compared between the two treatment groups (three-injection and four-injection groups). In addition, the baseline parameters associated with the risk of lesion reactivation were investigated.</p> Results <p>Seventy-seven patients were included in the study (35 in the three-injection group and 42 in the four-injection group). Lesion reactivation was observed in 72.7% of patients (56 patients) at a mean of 5.1 ± 2.3 months after the loading injections. The incidence was 74.3% with a mean time to reactivation of 5.6 ± 2.9 months in the three-injection group; it was 71.4% with a mean of 4.6 ± 1.7 months in the four-injection group. No significant difference was noted in lesion reactivation between the two groups (<i>P</i> = 0.983). A greater baseline central retinal thickness was significantly associated with an increased risk of lesion reactivation (<i>P</i> = 0.010).</p> Conclusions <p>Administering four loading injections of faricimab may not offer a clear advantage over three injections in suppressing lesion reactivation. A treat-and-extend regimen may be more appropriate in cases with marked retinal edema than an as-needed regimen to prevent further visual deterioration.</p>