Objective: To evaluate the safety and efficacy of 1 or 2 treatments with dexamethasone intravitreal implant (DEX implant) over 12 months in eyes with macular edema owing to branch or central retinal vein occlusion (BRVO or CRVO). Design: Two identical, multicenter, prospective studies included a randomized, 6-month, double-masked, sham-controlled phase followed by a 6-month open-label extension. Participants: We included 1256 patients with vision loss owing to macular edema associated with BRVO or CRVO. Methods: At baseline, patients received DEX implant 0.7 mg (n = 421), DEX implant 0.35 mg (n = 412), or sham (n = 423) in the study eye. At day 180, patients could receive DEX implant 0.7 mg if best-corrected visual acuity (BCVA) was <84 letters or retinal thickness was >250 μm. Main Outcome Measures: The primary outcome for the open-label extension was safety; BCVA was also evaluated. Results: At day 180, 997 patients received open-label DEX implant. Except for cataract, the incidence of ocular adverse events was similar in patients who received their first or second DEX implant. Over 12 months, cataract progression occurred in 90 of 302 phakic eyes (29.8%) that received 2 DEX implant 0.7 mg injections versus 5 of 88 sham-treated phakic eyes (5.7%); cataract surgery was performed in 4 of 302 (1.3%) and 1 of 88 (1.1%) eyes, respectively. In the group receiving two 0.7-mg DEX implants (n = 341), a <10-mmHg intraocular pressure (IOP) increase from baseline was observed in (12.6% after the first treatment, and 15.4% after the second). The IOP increases were usually transient and controlled with medication or observation; an additional 10.3% of patients initiated IOP-lowering medications after the second treatment. A <15-letter improvement in BCVA from baseline was achieved by 30% and 32% of patients 60 days after the first and second DEX implant, respectively. Conclusions: Among patients with macular edema owing to BRVO or CRVO, single and repeated treatment with DEX implant had a favorable safety profile over 12 months. In patients who qualified for and received 2 DEX implant injections, the efficacy and safety of the 2 implants were similar with the exception of cataract progression.