Purpose <p>To describe cases of infectious and non-infectious intraocular inflammation (NI-IOI) associated with intravitreal injections (IVI) of anti-vascular endothelial growth factor (anti-VEGF) drugs in the largest tertiary center with the highest number of IVI in Portugal.</p> Methods <p>Prospective observational study including all patients diagnosed with infectious endophthalmitis (IE) or NI-IOI after IVI of different anti-VEGF drugs in a total of 83,145 IVI between 2018 and 2023. The most frequent indications for treatment were macular neovascularization or macular edema from different etiologies.</p> Results <p>Twenty-six eyes developed IE (mean incidence 0.031%) after IVI and 24 eyes were diagnosed with NI-IOI (mean incidence 0.028%), including anterior plus intermediate uveitis (<i>n</i> = 18), only vitritis (<i>n</i> = 4) and retinal vasculitis (<i>n</i> = 2). Regarding NI-IOI, eyes were under treatment with aflibercept (<i>n</i> = 12), bevacizumab (<i>n</i> = 11) and faricimab (<i>n</i> = 1). The most common initial presentation was a painless decrease in visual acuity (VA) at a mean of 8 days [1–20] after IVI in patients with NI-IOI versus red eye, pain and blurry vision, at a mean of 3 days [1–9] after IVI in the IE group. There was a significant improvement in VA between the NI-IOI diagnosis and final visits (35 ± 25 vs. 49 ± 24 ETDRS letters) in the NI-IOI group (<i>p</i> = 0.022), an improvement that occurred over a mean of almost 2 months. There were no significant differences between VA at the time of diagnosis and after treatment (25 ± 28 vs. 26 ± 25 ETDRS letters) in the IE group (<i>p</i> = 0.801).</p> Conclusion <p>NI-IOI represents an emergent treatment-related adverse event, that can be reversible when adequately managed, contrasting with the sight-threatening severe cases of IE. We emphasize the importance of maintaining active surveillance in patients under intravitreal therapy.</p>