Since methylcytosine is relatively unstable, a deficiency of CpG dinucleotides and accumulation of mutations that manifest as TpG (and its complement CpA) is a diagnostic feature of higher eukaryotic DNA sequences subjected to methylation by DNA (cytosine-5) methyltransferases. Latent viral genomes may also be affected by DNA methylation in their host cells. We calculated, therefore, frequencies of dinucleotides in 20 completely sequenced herpesvirus genomes. We found a relative deficiency of CpG dinucleotides and a surplus of TpG + CpA dinucleotides in all lymphotropic gammaherpesvirus genomes except for two strains of rhesus rhadinovirus. DNAs of two strains of human herpesvirus 7, a betaherpesvirus targeting helper T cells, and equine herpesvirus 4, an alphaherpesvirus residing in the lymphoreticular system, also had a moderate CpG deficiency and TpG + CpA surplus. In contrast, most members of Alpha-, and Betaherpesvirinae subfamilies contained a relative surplus of CpG dinucleotides in their DNAs. Our data are consistent with the idea that methylated latent genomes are involved, after reactivation and productive replication, in the natural transmission cycle of most members of Gammaherpesvirinae and certain lymphotropic members of Alpha- and Betaherpesvirinae.