PURPOSE: To evaluate the efficacy and safety of intravitreal aflibercept injections for treatment of macular edema secondary to central retinal vein occlusion (CRVO). DESIGN: A randomized, multicenter, double-masked phase 3 study. PARTICIPANTS: A total of 177 treatment-naive patients with macular edema secondary to CRVO were randomized in a 3:2 ratio. METHODS: Patients received either 2-mg intravitreal aflibercept or sham injections every 4 weeks for 20 weeks. From week 24 to 48, the aflibercept group received aflibercept as needed (pro re nata [PRN]), and the sham group continued receiving sham injections. MAIN OUTCOME MEASURES: The primary efficacy end point was the proportion of patients who gained 15 letters or more in best-corrected visual acuity (BCVA) at week 24. This study reports week 52 results including the proportion of patients who gained 15 letters or more in BCVA and the mean change from baseline BCVA and central retinal thickness. Efficacy end points at week 52 were all exploratory. RESULTS: At week 52, the mean percentage of patients gaining 15 letters or more was 60.2% in the aflibercept group and 32.4% in the sham group (P = 0.0004). Aflibercept patients, compared with sham patients, had a significantly higher mean improvement in BCVA (+16.9 letters vs. +3.8 letters, respectively) and reduction in central retinal thickness (-423.5 μm vs. -219.3 μm, respectively) at week 52 (P < 0.0001 for both). Aflibercept patients received a mean of 2.5 injections (standard deviation, 1.7 injections) during PRN dosing. The most common ocular adverse events in the aflibercept group were related to the injection procedure or the underlying disease, and included macular edema (33.7%), increased intraocular pressure (17.3%), and eye pain (14.4%). CONCLUSIONS: Treatment with intravitreal aflibercept provided significant functional and anatomic benefits after 52 weeks as compared with sham. The improvements achieved after 6 monthly doses at week 24 largely were maintained until week 52 with as-needed dosing. Intravitreal aflibercept generally was well tolerated.