Published work (D. J. McGeoch, Nucleic Acids Res. 18:4105-4110, 1990; J. E. McGeehan, N. W. Depledge, and D. J. McGeoch, Curr. Protein Peptide Sci. 2:325-333, 2001) has indicated that evolution of dUTPase in the class of herpesviruses that infect mammals and birds involved capture of a host gene followed by a duplication event that resulted in a coding region comprising two fused dUTPase domains. Some of the conserved residues required for enzyme activity were then lost, resulting in a dUTPase containing a single active site with different elements contributed by each half of the protein. Further conserved residues were lost in one subfamily (the Betaherpesvirinae), yielding a protein that is related to herpesvirus dUTPases but has a different and as yet unrecognized function. Evidence from sequence similarities and structural predictions now indicates that several additional genes were derived from the herpesvirus dUTPase gene, probably by duplication. These are UL31, UL82, UL83, and UL84 in human cytomegalovirus (and counterparts in other members of the Betaherpesvirinae) and ORF10 and ORF11 in human herpesvirus 8 (and counterparts in other members of the Gammaherpesvirinae). The findings clarify the evolutionary history of these genes and provide novel insights for structural and functional studies.