Tumor necrosis factor (TNF) produces a dose-dependent inhibition of vesicular stomatitis virus (VSV), encephalomyocarditis virus (EMCV), and herpes simplex virus type 1 (HSV-1) replication in WISH cells. The antiviral activity of TNF against VSV and EMCV is greatly enhanced by combination with quercetin. Induction of 2',5'-oligo-adenylate (2-5A) synthetase by TNF is also enhanced by quercetin. Addition of polyclonal antibodies to human interferon (IFN)-beta completely blocked both enhancement of antiviral activity and 2-5A synthetase induction.