Intravitreal (IVT) injection of therapeutic agents has become one of the most commonly performed procedures in ophthalmology. Over the past decade, a number of guidelines have been published that recommend proper techniques to increase the safety of IVT injections. Among the various complications of IVT injections, endophthalmitis can be sight threatening. The reported endophthalmitis rates after IVT injection range from 0.020% to 0.085%, which are higher than what would be expected from a simple, fast, and relatively atraumatic procedure. The 2 key issues involved in the prevention of endophthalmitis are pre-IVT injection disinfection using povidone-iodine (PVI) and the use of topical antibiotics as prophylaxis. Whereas 5% PVI for 5 minutes is most commonly used in cataract surgery for disinfection, the duration in IVT injection is much less and can be as short as 30 seconds. Further studies seem warranted to investigate whether longer duration of PVI application in IVT injection can lower the endophthalmitis rate. Recent data suggest that there is inadequate evidence to support the routine use of prophylactic pre-, peri-, or postinjection antibiotics to reduce the risk of endophthalmitis. However, as many confounding factors such as the PVI regimens were not standardized in previous studies, it is too soon to make a concrete conclusion. Despite the availability of published guidelines, considerable variations still exist in real-life clinical situations. In this article, we describe our IVT injection practice protocol and compare it with the most recent international guidelines. Finally, a summary table that shows the clinical features of true, sterile, and pseudoendophthalmitis is presented.