Compositions and methods are provided for inhibiting the expression of human tumor necrosis factor-.alpha.-converting enzyme (TACE). Antisense oligonucleotides targeted to nucleic acids encoding TACE are preferred. Methods of using these oligonucleotides for inhibition of TACE expression and for treatment of diseases, particularly inflammatory and autoimmune diseases, associated with overexpression of TACE or TNF-.alpha. are provided.