Ranibizumab is a recombinant humanized monoclonal antibody Fab that neutralizes all active forms of VEGF-A. All three anti-VEGF agents have been proven promise in the treatment of various ocular neovascular diseases, such as age-related macular degeneration, diabetic retinopathy, and LY2157299 retinal vein occlusion. Because VEGF plays many roles in physiologic processes, its inhibition could have potentially serious systemic consequences. While the use of intravenous bevacizumab is recognized to be associated with an increased risk of arterial and venous thromboembolic events, it is controversial whether intravitreal anti-VEGF agents contribute to the development of arterial thromboembolic events, such as myocardial infarction and cerebrovascular accidents, common comorbidities leading to mortality in patients with ocular neovascular diseases. A pooled analysis from three randomized clinical trials that included 859 patients with age-related macular degeneration showed that intravitreal ranibizumab was associated with an increased risk of cerebrovascular accidents, when compared with sham treatment, whereas there was no apparent association between intravitreal ranibizumab and myocardial infarction. Because the number of patients included in this analysis is limited, the contribution of intravitreal anti-VEGF therapy to arterial thromboembolic events remains poorly defined. Recently, many more RCTs of intravitreal anti-VEGF therapy in ocular neovascular diseases have been performed. However, no significant association between intravitreal anti-VEGF therapy and arterial thromboembolic events has been shown in any RCTs. We hypothesized that these studies were not powered sufficiently to reveal a significantly increased risk due to the low incidences of arterial thromboembolic events. Therefore, we performed a systematic review of the published RCTs for a meta-analysis to determine the risk of arterial thromboembolic events associated with intravitreal anti-VEGF treatment. The results of this programme of prospectively designed overviews of data from 13 randomized clinical trials revealed that, as compared with control, intravitreal anti-VEGF therapy was not associated with the risk of arterial thromboembolic events, non-fatal cerebrovascular accidents, non-fatal myocardial infarction, and vascular death. The previous meta-analyses suggested the use of intravenous bevacizumab was recognized to be associated with an increased risk of arterial and venous thromboembolic events. Because of the high association of the risk of cardiovascular events with age-related macular degeneration, diabetes, and retinal vein occlusion, the results of a previous meta-analysis, which revealed intravitreal anti-VEGF was also associated with an increased risk of cerebrovascular accidents, was worrisome. However, another previous systematic review, as well as two non-randomized studies, suggested that intravitreal anti-VEGF use was not associated with increased risks of mortality, myocardial infarction, or stroke. Therefore, the success to detect such an increase in cerebrovascular accidents risk is likely due to the limited number of trials included for the analysis. Furthermore, risk ratios might be affected by small changes in the classification of events, due to the results based on a relatively small number of events. In the overview for arterial thromboembolic events, no difference in this risk between the arms receiving intravitreal anti-VEGF and control, with the 95% confidence interval included an up to 19% increased risk of arterial thromboembolic events down to a 36% reduction with intravitreal anti-VEGF.