To develop antirabies virus-specific agents, eight oligodeoxynucleotides (ODN) complementary to either rabies virus genomic RNA (negative polarity) or rabies virus transcripts (mRNA) were synthesized and tested for their activity to inhibit rabies virus infection in cell cultures. It was found that the ODN RH+1 complementary to rabies virus genomic RNA blocked almost completely rabies virus infection at concentrations as low as 2 microM, whereas ODN complementary to viral transcripts did poorly even at concentrations as high as 20 microM. The antigenomic ODN also has the ability to inhibit cell-to-cell spread of rabies virus, which is an indicator for protection of rabies virus infection in vivo. These results indicate that ODN complementary to rabies virus genomic RNA have strong ability to inhibit rabies virus infection in cell culture and may have the potential to be used for therapy in clinical rabies.