Background This study aimed to assess the influence of vitreoretinal interface (VRI) on the outcome of Brolucizumab intravitreal injections (IVBr) in patients with age-related macular neovascularization (MNV). Methods 40 eyes of 40 patients with active-naive MNV candidates to IVBr were enrolled at the Ophthalmology Clinic of the University “G. d’Annunzio,” Chieti-Pescara, Italy. Based on the VRI condition, 20 patients were included in the G0 group (without evidence of VRI alterations), whereas 20 patients were enrolled in the G1 group (with VRI abnormalities). The primary outcome measures were changes in best-corrected visual acuity (BCVA), central macular thickness (CMT), subfoveal choroidal thickness (SCT), pigment epithelial detachment presence and maximum height (PEDMH), intraretinal fluid (IRF) presence, subfoveal subretinal fluid (SSRF) presence and thickness (SSRFT), subretinal pigment epithelium fluid (SRPEF) presence and SRPEF thickness (SRPEFT). Results There were no significant differences in BCVA and SCT between the two groups, although both parameters significantly changed over time (BCVA p 0.005; SCT p < 0.001). No differences in CMT and PEDMH were found between the two groups. SSRF presence showed differences between the two groups at T4 (p 0.044), and IRF presence showed significant differences over time (p 0.008) in favor of MNV eyes without VRI alterations. Conclusions Concomitant vitreomacular interface disease alterations in eyes treated with IVBr for MNV influenced fluid presence with greater persistence of SSRF and IRF compared to MNV eyes without VRI. Nevertheless, the overall macular thickness and visual function were not significantly different between the two groups.