In this retrospective study the authors compare the risk for post-injection endophthalmitis between different anti-vascular endothelial growth factor (VEGF) agents and syringe preparation technique. This multicentre study included 197,402 injections. The drugs included in this study were three Anti-VEGF agents – bevacizumab, ranibizumab, and aflibercept. There were four types of the syringe-filling technique – prefilling by a hospital pharmacy, prefilling by a good manufacturing practice (GMP) pharmacy, self-drawing from the vial by the injecting physician, and use of a prefilled syringe. One hundred and forty-three thousand, three hundred and eighteen (72.6%) received bevacizumab injections, 28,906 (14.6%) ranibizumab injections, and 25,178 (12.8%) aflibercept injections respectively. The indications for intravitreal injections included age-related macular degeneration in 39 (73.6%) cases, diabetic macular oedema in six (11.3%) cases, retinal vascular occlusions in six (11.3%) cases, and other diseases in two (3.8%) cases. A total of 53 cases of post-injection endophthalmitis occurred. These included 31 (58.4%) women and 22 (41.6%) men, with a mean age of 75.2 ±12.2 years (range 33-97 years). Patients who suffered from endophthalmitis underwent 11.1 ±12.3 previous intravitreal injections (range 1-34). There was no correlation between number of previous injections nor age with the occurrence of endophthalmitis. Mean follow-up from presentation with endophthalmitis was 20.2 ±17.6 months. 29 (54.7%) cases following bevacizumab injections, 10 (18.9%) cases following ranibizumab injections, and 14 (26.4%) cases following aflibercept injections. The overall risk of post-injection endophthalmitis was 0.027% (1:3,725). The overall risk of post-injection endophthalmitis was 0.027% (1:3,725). The rate of post-injection endophthalmitis was 0.02% (1:4,942) with bevacizumab, 0.34% (1:2,892) with ranibizumab, and 0.055% (1:1,798) with aflibercept. The rate of endophthalmitis following aflibercept injections was significantly higher than that following bevacizumab injections (p = 0.001). There was no statistically significant difference between the rates of endophthalmitis following aflibercept and ranibizumab injections (p = 0.24) nor between the rates of endophthalmitis following bevacizumab and ranibizumab injections (p = 0.13). Of the bevacizumab injections, 31,627 were prefilled by a hospital pharmacy and 111,691 were prefilled by a GMP pharmacy. There were six cases of endophthalmitis following bevacizumab injections prefilled by a hospital pharmacy (0.019%, or 1:5,271) and 23 cases following bevacizumab injections prefilled by a GMP pharmacy (0.02%, or 1:4,856), with no significant difference between these rates (p = 0.85). Of the ranibizumab injections, 14,729 were drawn by the injecting physician and 14,177 were performed with a prefilled syringe. Of the 10 endophthalmitis cases, eight occurred in the self-drawn injections (0.054%, or 1:1,841) and two following the use of prefilled syringes (0.014%, or 1:7,238). There was also no difference in the rates of positive cultures between the different anti-VEGF agents (p = 0.39) or time periods (p = 0.76). A trend was noted toward a lower rate of endophthalmitis with prefilled syringes (0.019% verses 0.055%, p < 0.0001). The authors recommend the use of pre-filled syringes as these may be timesaving and help improve safety reduce infections. Limitations: Retrospective nature, no standardisation of injection techniques, as administered by numerous physicians with different levels of expertise. Strengths: Large multicentre study including all three available Anti-VEGFs.