Tumor Necrosis Factor (TNF) is a cytokine that induces necrotic and apoptotic forms of cell death. The TNF-induced signalling mechanisms leading to necrosis or apoptosis are partially distinct, and are therefore likely to be regulated in a different way. The zinc finger protein A20 is a TNF-induced primary response gene that has been shown to inhibit TNF-induced apoptosis. However, its ability to inhibit the necrotic route of cell death as well as the underlying mechanism remains unknown. Here we show that stable expression of A20 or a fusion protein consisting of Green Fluorescent Protein (GFP) and A20 protects the TNF-sensitive fibroblast cell line L929 partially from TNF-induced necrotic cell death. TNF-induced necrosis has been shown to involve the activation of several phospholipases, as well as an increased production of reactive oxygen radicals. The reduced TNF-sensitivity of A20-expressing L929 cells was correlated with a decrease of TNF-induced phospholipase A2 (PLA2), phospholipase C (PLC) and phospholipase D (PLD) activation. Furthermore, production of mitochondrial reactive oxygen intermediates was retarded by overexpression of A20. These results demonstrate that A20 not only inhibits TNF-induced apoptosis but also TNF-induced necrosis, suggesting that it interferes with an early step in TNF signalling which is required for both types of cell death.