AIM: To investigate changes in the rabbit retina after short-term and small amounts tamponade of perfluorooctane (PFO). METHODS: New Zealand rabbits were used, and 48 eyes were randomly and evenly assigned into four different groups. The PFO groups received a residue of 0.1 mL of PFO for ophthalmic surgery or 0.1 mL of F-Octane at the end of surgery; eyes from the pars plana vitrectomy (PPV) group were filled with balanced salt solution and those having not received surgical intervention served as controls. Eyes were collected at 1, 4 and 12wk and studied. RESULTS: Under a microscope, nuclear counts of the inner nuclear layer (INL) and outer nuclear layer (ONL) did not differ among the four groups at all time points; however, slight disarrangement of the ONL and occasional vacuolization of the INL were found in the inferior retina only at 12wk in two PFO groups. Four of the groups had similar results of Caspase-3 and TNF-α staining at all time points. Alternatively, IL-8 was increased in PFOa and PPV control groups at 4wk and in all three PPV groups at 12wk; also, the apoptotic index (%) was similarly increased in all three PPV groups at 4 and 12wk. CONCLUSION: Both PFOs are well tolerated in rabbit eyes for up to 12wk, which suggests that they can be used safely as intraoperative tools or for short-term and small amounts tamponade after surgery.