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As treatment paradigms have evolved toward chronic, often lifelong therapy with repeated injections, attention has increasingly shifted from short-term procedural safety to a broader evaluation of ocular and systemic adverse events. Among these, intraocular inflammation (IOI) has emerged as the most debated ocular safety signal, ranging from mild, self-limited sterile inflammation to rare but vision-threatening occlusive retinal vasculitis. At the same time, systemic adverse events remain biologically plausible yet uncommon in the general population. This review provides a contemporary, clinically oriented synthesis of anti-VEGF safety, emphasizing that IOI and systemic events are not uniform drug effects but reflect complex interactions among drug-specific properties, delivery factors, disease substrate, patient susceptibility, and immunogenicity. We outline a mechanistic framework distinguishing acute sterile inflammation driven by innate immune activation from delayed vasculitic phenotypes associated with adaptive immune responses and anti-drug antibodies. A structured five-pillar susceptibility model is proposed to contextualize risk modifiers, alongside phenotype-driven management and prevention strategies. Systemic safety considerations are reviewed with attention to agent-specific pharmacokinetics, high-risk patient phenotypes, and cumulative exposure. By integrating mechanistic insights with clinical phenotyping, risk stratification, and preventive strategies, this review aims to support informed, individualized decision-making. A balanced, prevention-focused approach enables clinicians to preserve the transformative benefits of anti-VEGF therapy while maintaining a high standard of long-term ocular and systemic safety.<\/jats:p>","DOI":"10.4103\/ijo.ijo_3284_25","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T10:00:19Z","timestamp":1770804019000},"page":"748-759","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":0,"title":["Anti-VEGF safety in evolution: A comprehensive review of ocular and systemic considerations"],"prefix":"10.4103","volume":"74","author":[{"given":"Ramesh","family":"Venkatesh","sequence":"first","affiliation":[{"name":"Department of Vitreo-retinal Services, Narayana Nethralaya, Bangalore, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Preksha","family":"Biradar","sequence":"additional","affiliation":[{"name":"Department of Vitreo-retinal Services, Narayana Nethralaya, Bangalore, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaurav","family":"Malwe","sequence":"additional","affiliation":[{"name":"Department of Vitreo-retinal Services, Narayana Nethralaya, Bangalore, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vishma","family":"Prabhu","sequence":"additional","affiliation":[{"name":"Department of Vitreo-retinal Services, Narayana Nethralaya, Bangalore, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prathibha","family":"Hande","sequence":"additional","affiliation":[{"name":"Department of Vitreo-retinal Services, Narayana Nethralaya, Bangalore, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rupal","family":"Kathare","sequence":"additional","affiliation":[{"name":"Department of Vitreo-retinal Services, Narayana Nethralaya, Bangalore, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pragati","family":"Raj","sequence":"additional","affiliation":[{"name":"Department of Vitreo-retinal Services, Narayana Nethralaya, Bangalore, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rupak","family":"Roy","sequence":"additional","affiliation":[{"name":"Department of Vitreo-retina, Aditya Birla Sankara Nethralaya, Kolkata, West Bengal, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naresh K","family":"Yadav","sequence":"additional","affiliation":[{"name":"Department of Vitreo-retinal Services, Narayana Nethralaya, Bangalore, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaitra","family":"Jayadev","sequence":"additional","affiliation":[{"name":"Department of Vitreo-retinal Services, Narayana Nethralaya, Bangalore, Karnataka, 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