PURPOSE. To identify the role of the fragment crystallizable (Fc) region in determining intraocular protein drug pharmacokinetics. METHODS. We generated a new VEGF-Trap lacking the Fc region (FcfVEGF-Trap, MWt = 100 kDa) by replacing the Fc region of native VEGF-Trap (MWt = 145 kDa) with a dimerized coiled-coil domain. Forty-two rabbits were injected intravitreally with VEGF-Trap or FcfVEGF-Trap (n = 21 each) in one of the eyes, harvested at six time points (1 hour and 1, 2, 4, 14, and 30 days after injections). VEGF-Trap and FcfVEGF-Trap concentrations in the vitreous, aqueous humor, and retina/choroid were measured, and drug pharmacokinetic properties were analyzed. RESULTS. In all three ocular compartments, the maximal concentrations for both FcfVEGF-Trap and VEGF-Trap were observed at 1 hour after injection. Half-lives of FcfVEGF-Trap in the vitreous and retina/choroid (145.02 and 102.12 hours, respectively) were 1.39 and 2.30 times longer than those of VEGF-Trap (103.99 and 44.42 hours, respectively). Total exposure of the aqueous humor and retina/choroid to FcfVEGF-Trap was 13.2% and 39% of the vitreous exposure, respectively, whereas VEGF-Trap concentrations were 25.2% and 26.2%, indicating that FcfVEGF-Trap shows a preference for posterior distribution and elimination. CONCLUSIONS. FcfVEGF-Trap, despite its lower molecular weight, showed longer half-lives in vitreous and retina/choroid than VEGF-Trap did, suggesting that Fc receptors in ocular tissues contribute to anti-VEGF drug elimination. Truncation or mutation of the Fc region can prolong the intraocular residence time of VEGF-Trap and possibly reduce the number of VEGF-Trap injections required in clinical practice.