Purpose. This study was designed to evaluate the intraocular distribution and metabolism of the antiviral nucleotide analogs cidofovir and cyclic l-[(S)-3-hydroxy-2-(phosphonomethoxy) propyljcytosine (HPMPC) in New Zealand white rabbits following intravitreal administration.Methods. Male rabbits received either14C-cidofovir or14C-cyclic HPMPC by intravitreal injection into both eyes (50μg/eye, 11μCi/eye). Two animals per group were sacrificed at 24, 48, 72 or 240 h post-dose. Ocular tissues, kidney and liver were oxidized to determine total radioactivity and metabolites were determined by HPLC.Results. At 24 h post-dose, total radioactivity was 9.96 and 5.18μg-equiv/g for cidofovir and cyclic HPMPC, respectively, in vitreous and 20.9 and 3.54μg-equiv/g, respectively, in retina. Although the initial vitreal clearance was 2-fold faster for the cyclic analog, the estimated terminal elimination half-lives in vitreous (42 hr) and in retina (66-77 hr) were similar for both drugs. By 240 h post-dose, radioactivity in all ocular tissues was approximately ten-fold higher for cidofovir. Radioactivity in vitreous at 240 h after intravitreal dosing with either drug contained cidofovir, cyclic HPMPC and cidofovir-phosphocholine.Conclusions. The long retinal half-life observed presumably reflects formation of phosphorylated cidofovir within retinal cells. Cidofovir achieved a ten-fold higher level of phosphorylated drug in retina than cyclic HPMPC. Therefore, intravitreal cidofovir may be expected to suppress progression of retinitis for a longer period than an equivalent intravitreal dose of cyclic HPMPC. The intravitreal half-life of cidofovir was 20-fold longer than that of ganciclovir in the same animal model.