The nucleotide changes of the DNA polymerase gene and the susceptibility of acyclovir (ACV)-resistant varicella-zoster virus (VZV) mutants to anti-herpetic drugs were determined and compared to those of herpes simplex virus type 1 (HSV-1) mutants. The seven ACV-resistant VZV mutants were classified into three groups, N(779)S, G(805)C and V(855)M, according to the sequences of their DNA polymerase genes. The amino acid substitutions N(779)S and G(805)C were identical in position to the N(815)S and G(814)C mutations in the HSV-1 DNA polymerase mutants, respectively, and the V(855)M amino acid substitution was similar to the HSV-1 V(892)M mutation. All three groups of VZV mutants were susceptible to ACV, phosphonoacetic acid, vidarabine and aphidicolin, at levels similar to those seen with the respective HSV-1 mutants, except for subtle differences that were due possibly to the non-conserved regions in their sequences. Although both the HSV-1 and the VZV DNA polymerase genes show 53% sequence similarity, both viruses essentially show a similar biochemical behaviour.