Antisense oligonucleotides were modified by their ends with hydrophobic substituents which permitted enhancing their activity. The effect of hydrophobized oligonucleotides on reproduction of Herpes Simplex Virus type 1 in Vero cells was studied. Two types of oligonucleotides were used: a 12-mer complementary to the splicing site 983-994 of early mRNA-5 of the virus and 19-mer complementary to the site of mRNA that encodes the virus DNA-polymerase. These oligonucleotides were modified by 5'-ends with n-undecyl or cholesteryl moieties and by 3'-ends with acridine or 1,7-heptanediol. In comparison with the unmodified oligonucleotides the hydrophobized ones were significantly more active and inhibited HSV-1 infection at micromolar concentrations.