The antiviral, antiproliferative, and natural killer (NK) cell activation by recombinant human interferon-consensus (IFN-Con1) has been compared with that of two other type I IFNs: IFN-alpha 2a (Roferon) and IFN-alpha 2b (Intron A). The specific activity (antiviral units/mg) of IFN-Con1 was 10-fold higher than that of the other two IFNs in the vesicular stomatitis virus (VSV)-HeLa antiviral assay. The antiproliferative activity on a molar basis of IFN-Con1 on Daudi cells and Eskol (a human leukemic hairy cell-like cell line) was significantly greater than that of IFN-alpha 2a and IFN-alpha 2b. IFN-Con1 also enhanced or induced NK cell killing of target cells to a greater extent than that of IFN-alpha 2a and IFN-alpha 2b. However, on antiviral unit basis, the activities were similar. These results would suggest that IFN-Con1 may be more effective at lower protein concentrations in clinical applications than other available IFNs.