The influence of interferon alpha and gamma alone or in combination on the augmentation of human natural cytotoxicity was studied. Treatment of peripheral blood lymphocytes with IFN-α led to a rapid augmentation of NK activity, in contrast to IFN-γ where target cell killing was observed only following 18 hrs exposure of lymphocytes to IFN-γ. The results of the single cell assay paralleled those obtained using the Chromium release test, but neither interferon type caused an increase in the number of target binding lymphocytes. The combined effect of IFN-α and IFN-γ in stimulating human natural cytotoxicity demonstrated individual lymphocyte responses to be variable. Exposure of lymphocytes to IFN-α and IFN-γ for 18 hrs prior to assay for cytotoxicity usually decreased the level of cytotoxicity compared with control values, whereas other treatment regimes gave an additive and sometimes synergistic effect. Only treatment with IFN-α for 18 hrs and IFN-γ for one hr produced a synergistic response in the majority of individuals tested. We conclude from this study that individual responses to IFN-α and IFN-γ alone or in combination are variable and dependent upon timing of exposure of lymphocytes to individual interferon types, and possibly reflects the donor status at the time of sampling.