The biosynthesis of interleukin-6 receptor (IL-6R) and gp130 in vitro was blocked using specific antisense oligonucleotides (ASO) in HepG2 liver cells and the efficacy of various ASOs was tested on the generation of IL-6-induced junB mRNA. We used three ASOs specific for the IL-6 receptor, three specific for gp130 and a control (nonsense) oligonucleotide specific for ∍-chain of IgE (not expressing in HepG2 cells). Our data indicate that a gp130-specific ASO,g2, was the most effective blocker of IL-6-induced junB mRNA, whilst the IL-6 receptor ASOs alone were ineffective. The mechanism of gene inactivation by ASO treatment was partially elucidated by demonstration of the loss of gp130 mRNA from cells treated with ASOs showing functional efficacy. Our data may help to design antisense oligonucleotides that are effective in therapy (e.g. as anti-inflammatory agents) in the future.