We describe inhibition of HIV replication by a partially double-stranded 54mer oligodeoxynucleotide, ODN, which consists of an antisense strand targeting the highly conserved polypurine tract, PPT, of HIV, and a second strand, compatible with triple-helix formation. Upon treatment of HIV-infected cells with ODN early after infection no viral nucleic acids, syncytia or p24 viral antigen expression was observed. The ODNmediated effect was highly sequence-specific. The ODN against HIV-IIIB was effective preferentially against its homologous PPT and less against the PPT of HIV-BaL differing in two of 24 nucleotides and vice versa. It may be interesting mechanistically as an antiviral drug.