Cytomegalovirus (CMV) resistance to ganciclovir occurs via mutations in the UL97 gene. CMV DNA, from vitreous and blood specimens and from culture isolates from 87 patients with acquired immunodeficiency syndrome and CMV retinitis who received a ganciclovir implant, was sequenced to identify the relationship between the UL97 DNA sequences in the eye and peripheral blood. There was 93.5% agreement between the UL97 gene sequences from paired vitreous specimens and blood specimens. Sequence analysis of vitreous specimens showed that 15% (13/87) of the patients had either a ganciclovir resistance-conferring mutation or a polymorphism in the CMV UL97 gene. Eleven of the 13 mutations or polymorphisms in the vitreous also were identified in blood. Although the number of mutations limits definitive interpretation, these data suggest that blood specimens may reflect the events occurring in the eyes of patients with CMV retinitis.