Recent studies have shown that interferon-gamma (IFN-gamma) synergizes with IFN-alpha/beta to inhibit the replication of both RNA and DNA viruses. We investigated the effects of IFNs on the replication of two strains of severe acute respiratory syndrome-associated coronavirus (SARS-CoV). While treatment of Vero E6 cells with 100 U/ml of either IFN-beta or IFN-gamma marginally reduced viral replication, treatment with both IFN-beta and IFN-gamma inhibited SARS-CoV plaque formation by 30-fold and replication by 3000-fold at 24 h and by > 1 x 10(5)-fold at 48 and 72 h post-infection. These studies suggest that combination IFN treatment warrants further investigation as a treatment for SARS.