Background To report on the current methods for choroidal neovascularization (CNV) detection and the clinical outcome of intravitreal therapies in patients with neovascular pigment epithelium detachment (PED). Methods Retrospective, interventional cohort study on 77 eyes of 59 patients. Inclusion criteria were a neovascular PED, identified by fluorescence angiography (FA) or/and optical coherence tomography angiography (OCTA) treated with aflibercept (16 eyes) or ranibizumab monotherapy (36 eyes) or with at least three injections of ranibizumab, with a therapy switch to aflibercept in case of persistent fluid (25 eyes). The therapy regimen was a pro re nata (PRN) scheme with an upload phase of three monthly injections. Outcome measures were sensitivity of CNV detection and evaluation of CNV activity at baseline on FA compared to OCTA, the change in highest retinal prominence (HRP) and PED size, assessed by spectral - domain OCT (SD-OCT), and the change in best-corrected visual acuity (BCVA) three months after therapy initiation in the monotherapy groups or after the switch. Results Sensitivity of CNV detection was slightly superior for FA (0.786) compared to OCTA (0.706), whereas CNV activity evaluation was superior on OCTA. HRP significantly decreased after aflibercept (p<0.001) or ranibizumab monotherapy (p<0.001), and after therapy switch to aflibercept (p<0.001) in ranibizumab refractory patients. Corresponding BCVA improved in these groups, but without statistical significance (p=0.46; p = 0.11; p=0.19). PED size significantly decreased after aflibercept monotherapy (p=0.001) or after therapy switch to aflibercept (p<0.001), but not after ranibizumab. Conclusions The combination of FA and OCTA offers significantly improved visualisation, quantification, and predictability of CNV activity in neovascular PED. Aflibercept and ranibizumab are effective treatment options for neovascular AMD with PED, with a stronger effect of aflibercept on the PED itself. Furthermore, aflibercept appears to be a valuable tool for the management of patients unresponsive to ranibizumab.