The most severe visual impairments due to age-related macular degeneration (AMD) are frequently caused by the occurrence of choroidal neovascularization (CNV). Although photodynamic therapy with verteporfin (PDT-V) is currently a second-line treatment for neovascular AMD, it can be conveniently combined with drugs acting against vascular endothelial growth factor (anti-VEGF) to reduce the healthcare burden associated with the growing necessity of anti-VEGF intravitreal re-injection. Because the common 677 C > T polymorphism of the methylenetetrahydrofolate reductase gene (MTHFR-C677T; rs1801133) has been described as predictor of satisfactory short-term responsiveness of AMD-related CNV to PDT-V, we retrospectively examined the outcomes of 371 Caucasian patients treated with standardized, pro-re-nata, photodynamic regimen for 24 months. Responder (R) and non-responder (NR) patients were distinguished on the basis of the total number of scheduled PDT-V (TN-PDT-V) and change of best-corrected visual acuity (∆-BCVA). The risk for both TN-PDT-V and ∆-BCVA to pass from R to NR group was strongly correlated with CT and TT genotypes of MTHFR-C677T variant resulting, respectively, in odd ratios of 0.19 [95% CI, 0.12-0.32] and 0.09 [95% CI, 0.04-0.21] (P < 0.001), and odd ratios of 0.24 [95% CI, 0.15-0.39] and 0.03 [95% CI, 0.01-0.11] (P < 0.001). These pharmacogenetic findings indicate a rational basis to optimize the future clinical application of PDT-V during the combined treatments of AMD-related CNV, highlighting the role of thrombophilia to be aware of the efficacy profile of photodynamic therapy.