We have analyzed the protein and nucleic acid sequences of the DNA polymerase from herpes simplex virus type 1 (HSV-1) to provide insight into the expression and possible structure of this enzyme. Extensive similarity between the amino acid sequence and that of the Epstein Barr virus DNA polymerase is reported. We describe probable structural similarities between these proteins and the use of these similarities to define structural and functional domains within the polymerase. Analysis of base composition and codon usage reveals that several genes from HSV-1, including DNA polymerase, exhibit a strong preference for guanine or cytosine at the third codon position. This preference may result from the high guanine + cytosine content of the virus and produces a highly restricted codon usage, different from that of the host cell. Consequences of the unusual codon usage for viral expression include the potential for extensive mRNA secondary structure.