OBJECTIVE To determine whether there is a difference in anesthetic effect between topical proparacaine drops, 4% lidocaine solution, or 3.5% lidocaine gel, and whether this has an impact on the overall injection experience. METHODS One hundred and twenty sequential patients undergoing intravitreal injections were randomized to 1 of 3 groups: proparacaine 0.5% drops (Group 1), proparacaine + 4% lidocaine-soaked cotton tipped swabs (Group 2), or 3.5% lidocaine gel (Group 3). Discomfort associated with the lid speculum, with the needle, and with burning sensation was graded on a scale of 0 to 10 (0 = no pain, 10 = worst pain ever). The overall injection experience was graded as Excellent, Very Good, Fair, Poor, or Awful. RESULTS The average lid speculum pain score for Group 1 was 0.85, Group 2 was 0.50, and Group 3 was 0.65 (P = 0.32). The average needle pain score for Group 1 was 1.78, Group 2 was 1.75, and Group 3 was 1.48 (P = 0.38). The average burning pain score for Group 1 was 1.45, Group 2 was 1.58, and Group 3 was 1.13 (P = 0.23). Overall satisfaction was rated as Excellent or Very Good in 95%, 97.5%, and 92.5% of Group 1, 2, and 3 patients, respectively (P = 0.64). CONCLUSIONS The use of topical proparacaine drops provides very effective and cost-effective anesthesia during office-based intravitreal injections.