Injections of local anesthetics into pterygopalatine fossa gained popularity for treating acute and chronic facial pain and headaches. Injury of maxillary artery during pterygopalatine fossa injection can result in pseudoaneurysm formation or acute bleeding. We aimed to identify the optimal approach into pterygopalatine fossa by comparing feasibility and safety of suprazygomatic and two infrazygomatic approaches.We analyzed 100 diagnostic CT angiographies of cerebral arteries using 3D virtual reality. Each approach was determined as a target point in pterygomaxillary fissure and an array of outermost edges trajectories leading to it. The primary outcomes were feasibility and safety for each approach. The secondary outcome was the determination of maxillary artery position for each approach to identify the safest needle entry point.Suprazygomatic approach was feasible in 96.5% of cases, while both infrazygomatic approaches were feasible in all cases. Suprazygomatic approach proved safe in all cases, posterior infrazygomatic in 73.5%, and anterior infrazygomatic in 38%. The risk of maxillary artery puncture in anterior infrazygomatic approach was 14.7%±26.4% compared to 7.5%±17.2%. in posterior infrazygomatic with the safest needle entry point in the upper-lateral quadrant in both approaches.The suprazygomatic approach proved to be the safest, however not always feasible. The posterior infrazygomatic approach was always feasible and predominantly safe if the needle entry point was just anterior to the condylar process. The anterior infrazygomatic approach was always feasible, however least safe even with an optimal needle entry point just anterior to the coronoid process.