WISH and Hep-2 cells were incubated in an environment with atmospheric oxygen (20% O2, approximately 140 mmHg partial pressure), and under hypoxic conditions (2% O2, approximately 14 mmHg). The oxygen tension greatly affected the metabolism of the cells and their response to interferon-alpha (IFN-alpha) and IFN-gamma. Under hypoxic conditions, the cytopathogenicity of vesicular stomatitis virus (VSV) was reduced by about 50%, and the antiviral effects of the interferons (IFNs) were increased, both in terms of VSV-induced cytopathic effect (CPE), and yields of infectious virus. Local hypoxia is a nonspecific host defense against virus infection. The present results suggest that one of the mechanisms is by potentiation of the effects of the IFN produced at the sites of virus replication.