Tumour necrosis factor (TNF) and lymphotoxin were initially described as tumoricidal proteins that are produced by activated macrophages and lymphocytes, respectively. Since TNF and lymphotoxin are structurally related, bind to the same cell surface receptor and have indistinguishable biological activities, they have been designated as TNF-alpha and TNF-beta, respectively. The multiple activities of these molecules indicate their importance in immunoregulative responses. Here we report that both TNF-alpha and TNF-beta have antiviral activity and synergize with interferons (IFNs) in the induction of resistance to both RNA and DNA virus infection in diverse cell types. These effects of TNFs are not due to the induction of IFN synthesis. Virus-infected cells are selectively killed by TNFs and this activity is accelerated by IFN-gamma. The production of TNFs is induced by viruses, further suggesting the importance of TNFs in the physiological antiviral response.