Purpose <p>To compare safety, efficacy and patient experience when treated with intravitreal injections of a 30-gauge needle compared to a 34-gauge needle.</p> Methods <p>A Prospective Randomized controlled study in a single tertiary medical center. Patients were randomly assigned to receive prescheduled intravitreal injection with either a 30 or a 34-gauge needle. Intravitreal injections were performed by a senior vitreoretinal surgeon or by a resident. After the intravitreal injection was performed, patients were asked to grade pain sensation on a Visual Analog Scale (VAS score). In addition, the presence or absence of subconjunctival hemorrhage (SCH) was recorded, as well as any post-injection complications in the following month.</p> Results <p>Our cohort included 91 patients with a total of 114 injections. Mean age was 72.8 ± 12, with 51 females and 40 males. The mean pain score in the 30-gauge group was 3.17 ± 2.11 vs 3.05 ± 2.45 in the 34-gauge group. There was no statistically significant difference in the mean pain score among the two groups (<i>p</i> = 0.571) nor in gender (<i>p</i> = 0.563) overall. However, when the injections performed by a senior vitreoretinal surgeon, 34-gauge needles were statistically significantly less painful than 30-gauge needles (2.5 ± 2.0 vs. 3.4 ± 1.8; <i>p</i> = 0.04). Additionally, no difference was recorded in formation of SCH among the groups (<i>p</i> = 1).</p> Conclusion <p>The use of a 34-gauge needle was found to be less painful when used by a senior vitreoretinal surgeon and with similar safety profile as the 30 gauge needle. This may further improve patient satisfaction and increase treatment adherence.</p>