Neointima formation associated with vascular restenosis is a complex local inflammatory process actively involving the major cellular component of the atherosclerotic lesion, the vascular smooth muscle cell. NF-kB is a pleotrophic transactivator of a diverse group of genes whose activation has been strongly associated with the cellular response to inflammation. We treated human vascular smooth muscle cells (VSMC) with phosphorothio antisense oligonucleotides to the p65 subunit of NF-kB and report that addition of p65 antisense oligonucleotides (1-20 microM), but not sense or p50, inhibit human VSMC adherence and proliferation in a concentration-dependent manner. Additionally, administration of p65 antisense significantly inhibited neointima formation in balloon angioplasty treated rat carotid arteries, indicating that the p65 subunit of NF-kB transactivates genes whose expression is important in VSMC pathobiology. These results suggest that abrogation of p65 reduces neointima formation by inhibition of smooth muscle cell proliferation and adherence.