Purpose <p>Limited studies with big databases have investigated the frequency of full thickness macular holes as serious complication of intravitreal injections. To analyze the frequency and describe the impact on visual acuity of acute and delayed full thickness macular holes caused by intravitreal injection with VEGF-inhibitors.</p> Methods <p>3,316 patient files of patients who have been treated with intravitreal injections with VEGF-inhibitors during the period from August 2005 to December 2024 were screened for occurrence of full thickness macular holes. A total of 16 patients with full thickness macular holes under therapy with VEGF-inhibitors in our outpatient eye clinic were identified. For further analysis and comparison a separation into an acute and a delayed occurrence of full thickness macular holes was performed.</p> <p>Main outcome was the frequency of full thickness macular holes under VEGF-inhibitor therapy in a large consecutive single center cohort. Secondary endpoints were the visual acuity and structural OCT outcome after surgical treatment.</p> Results <p>Between August 2005 and December 2024 78,694 VEGF-inhibitor intravitreal injections in 3,316 patients and 4,474 eyes were performed. During this time 7 acute cases and 9 delayed cases of full thickness macular holes occurred. The relative risk was 0.02% per eye and intravitreal injection. In relation to the average number of intravitreal injections per treated eye, the relative risk was 0.16% for acute full thickness macular holes, 0.20% for delayed full thickness macular holes and 0.36% overall during an intravitreal injection course. All but one of the 16 patients were treated with pars plana vitrectomy and peeling of the inner limiting membrane. Even with adequate surgical therapy, the acute full thickness macular hole group remained with a more severe visual acuity loss than the delayed full thickness macular hole group (0.06 (20/333) vs. 0.4 (20/50); <i>p</i> =.006).</p> Conclusion <p>Even with paying crucial attention to the correct way of intravitreal injection administration, especially an acute macular hole remains a rare but threatening event for visual acuity in patients under VEGF-inhibitor therapy. Surgical treatment should be advised.</p> Key messages <p><Emphasis Type="BoldItalic">What is known</Emphasis><UnorderedList Mark="Bullet"> <ItemContent> <p>The frequency of full thickness macular hole development in eyes undergoing intravitreal injections with VEGF-inhibitors is expected to be low, but not well observed.</p> </ItemContent> </UnorderedList></p> <p><Emphasis Type="BoldItalic">What is new</Emphasis><UnorderedList Mark="Bullet"> <ItemContent> <p>In a monocentric consecutive series of 78,694 VEGF-inhibitor intravitreal injections the frequency of full thickness macular holes was 0.36% per eye for an average course</p> </ItemContent> <ItemContent> <p>Full thickness macular holes during intravitreal injection therapy with VEGF-inhibitors remain a rare adverse event with a higher risk compared to untreated eyes of the same age and a significant impact on visual function.</p> </ItemContent> </UnorderedList></p>