AIM: To investigate the feasibility and efficacy of tissue plasminogen activator (tPA) injection into the optic nerve as a treatment for retinal vein occlusion in rabbits. METHODS: Rose Bengal-mediated laser-induced retinal vein occlusions were produced in rabbit eyes. Fluorescein angiography (FA) was performed on each eye 3 days before laser irradiation and 30 minutes after laser irradiation. The treatment group (n =20 veins) received intra-optic nerve injection of tPA (12.5μg in 0.05mL BSS) and the controls (n = 24 veins) received 0.05mL BSS. FA was repeated to determine the recanalization of the vessel at 3 and 7 days after treatment, followed by histological examination. RESULTS: Rose Bengal-mediated laser-induced retinal vein occlusions were successfully developed and confirmed by FA. The incidence of the recanalization of the vessels in treatment animals was 70.0%, while 16.7% in the control animals (P = 0.001). CONCLUSION: Intra-optic nerve tPA injection increases the incidence of recanalization of the occluded vessels. Although further studies are needed, our data suggested that injection of tPA into the optic nerve may have a potential benefit in the treatment of central retinal vein occlusion.