It was demonstrated using self-replicating hepatitis C virus (HCV) RNAs that both types of interferons (IFNs) (in particular IFN-alpha and IFN-gamma) are potent inhibitors of HCV replication in Huh-7 cells. Because IFN-gamma and tumour necrosis factor (TNF)-alpha trigger a partially overlapping set of antiviral defence mechanisms, it is tempting to speculate that TNF-alpha also inhibits HCV replication. However, this study shows that TNF-alpha does not affect HCV protein and RNA synthesis, nor does it synergistically enhance the inhibitory effect of IFN-gamma. Taken together, these results demonstrate that HCV replication in Huh-7 cells is highly resistant to TNF-alpha. It is, therefore, unlikely that the increased production of TNF-alpha, which is seen in many hepatitis C patients, contributes to HCV clearance by inducing antiviral defence mechanisms in infected hepatocytes.