Nuclear factor-κB (NF-κB)/Rel transcription factors may be involved in atherosclerosis, as is suggested by the presence of activated NF-κB in human atherosclerotic lesions. The aim of the present study was to investigate the effects of oxidized LDL (oxLDL) on the NF-κB system in human THP-1 monocytic cells as well as adherent monocytes. Our results demonstrate that short-term incubation of these cells with oxLDL activated p50/p65 containing NF-κB dimers and induced the expression of the target gene IL-8. This activation of NF-κB was inhibited by the antioxidant and H₂O₂ scavenger pyrrolidine dithiocarbamate and the proteasome inhibitor PSI. The oxLDL-induced NF-κB activation was accompanied by an initial depletion of IκB-α followed by a slight transient increase in the level of this inhibitor protein. In contrast, long-term treatment with oxLDL prevented the lipopolysaccharide-induced depletion of IκB-α, accompanied by an inhibition of both NF-κB activation and the expression of tumor necrosis factor-α and interleukin-1β genes. These observations provide additional evidence that oxLDL is a potent modulator of gene expression and suggest that (dys)regulation of NF-κB/Rel is likely to play an important role in atherogenesis.