The present invention concerns double-stranded NF-.kappa.B decoy oligodeoxynucleotide (NF-.kappa.B dsODN) molecules that contain a core sequence capable of specific binding to an NF-.kappa.B transcription factor. In a particular aspect, the invention concerns NF-.kappa.B decoy molecules that preferentially bind p50/p65 and/or cRel/p50 heterodimers over p50/p50 homodimers. In another aspect, the invention concerns NF-.kappa.B decoy molecules with improved binding affinity to p65.