Interferon (IFN;titer, ≥10 units) was present in the acute-phase sera of 30 of 40 subjects with culture and/or serologically documented, naturally acquired influenza A/Brazil/78 (H1N1) and in the acute-phase sera of five of 27 subjects with an influenza-like illness of undetermined etiology. No statistical correlation existed between the quantity of IFN in acute-phase serum and the course of the clinical illness. Antiviral activity in all of nine acute-phase sera and three of four sera obtained on the fifth to seventh days of illness was neutralized to <50% by antibody to virus-induced human leukocyte IFN (HµIFN-α). In contrast, none of five sera collected between 21 and 23 days after the onset of illness contained IFN sensitive to neutralization by antibody to HµIFN-α. Resistance of IFN in convalescent-phase sera to neutralization by antibody to HµIFN-α suggests that multiple IFN species may evolve during viral infections.