Background and Objective: To determine whether patients prefer topical anesthesia or subconjunctival anesthesia for intravitreal injection.Patients and Methods: Consecutive patients receiving bilateral simultaneous injections of anti-vascular endothelial growth factor agents were asked to participate in this within-patient, prospective, single-blinded, randomized, factorial study. Fifty-seven patients completed the study. Both eyes were treated with topical anesthesia. One eye was also injected with subconjunctival lidocaine. Anesthesia for the next treatment visit was based on patient preference at the conclusion of the study visit and at a 4-hour and 24-hour follow-up telephone call. Patients were allowed to change their anesthesia preference during the next three visits. The final endpoint for the study was anesthesia preference for ongoing intravitreal injections.Results: Fifty patients (88%) preferred subconjunctival anesthesia and seven patients (12%) preferred topical anesthesia for ongoing treatments. (P = .0003) CONCLUSION: Given the choice, most patients prefer subconjunctival anesthesia to topical anesthesia for intravitreal injections.