Hybrid interferon DNA recombinants were constructed from the IFLrA and IFLrD leukocyte interferon-coding sequences. Each of the hybrid interferons was purified with the use of a monoclonal antibody to human leukocyte interferon. Three amino acid residues were identified, one or all of which function to potentiate antiviral activity on feline cells and reduce activity on human cells. Because at sufficiently high concentrations human interferons can interact with mouse and rat receptors, it is apparent that the species barrier is only relative and that interferons can be forced into heterologous receptors by mass action. In addition, the specific molecular antiviral and antiproliferative activities (molecules of interferon/cell required for a specific effect) for each of these interferons were determined. The specific molecular activities permit an accurate comparison of the efficacy of different interferons for a specific effect. Because the ratios of antiproliferative/antiviral activity of these interferons vary over a 12-fold range, it appears that the antiviral and antiproliferative activities are promulgated through different mechanisms. To account for these results, it is proposed that there are at least two distinct interferon receptors on cells.