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To investigate the long-term safety of intravitreal ziv-aflibercept in eyes receiving six or more intravitreal injections of ziv-aflibercept, an off-label substitute to the approved aflibercept.Consecutive patients with retinal disease receiving six or more of intravitreal 0.05 mL ziv-aflibercept (1.25 mg) injections were followed monthly in three centres. Outcome measures were best-corrected visual acuity (BCVA) (logarithm of the minimum angle of resolution (logMar)) and central macular thickness (CMT) on spectral domain optical coherence tomography and monitoring for ocular inflammation, progression of lens opacities and intraocular pressure rise. Paired comparison was done using Wilcoxon signed-rank test calculator.Sixty-five eyes of 60 consecutive patients received a mean of 8.4 (6–17) intravitreal injections with a baseline mean logMAR BCVA of 0.98±0.56 and CMT 432.7±163.0 μm and followed for a mean of 9.2 months (range 6–18 months). After the sixth injection, mean BCVA improved to 0.57±0.36 (p=0.001) and CMT decreased to 274.8±117.8 μm (p=0.0001). At the 9-month follow-up, mean BCVA improved to 0.62±0.37 (p=0.0004) and mean CMT decreased to 292.0±160.9 μm (p<0.01) in 19 eyes. At 1 year, mean BCVA was 0.73±0.52 and CMT 311.6±232.5 μm in seven eyes. Intraocular pressures did not increase after injections. One subject developed transient mild iritis at the fourth injection but not on subsequent injections. No lens opacity progression or endophthalmitis was noted. Systemic adverse effects were not registered.Repeated intravitreal injections of ziv-aflibercept appear tolerable, safe and efficacious in the therapy of retinal disease.