Prophylactic treatment of mice with interferon (IFN) or polyinosinic-polycytidylic acid [poly(I:C)], an IFN inducer, provided significant protection against an extracellular infection by Aspergillus fumigatus in both Swiss and Swiss athymic nude mice. Tunicamycin (TM) treatment inhibits the antifungal activity of IFN and poly(I:C) in these mice. Anti-asialo GM1 or TM [both inhibitors of natural killer (NK) cell function] treatment enhance the severity of A. fumigatus infection. These results suggest that NK cells may play a role in A. fumigatus infection and in the antifungal activity of IFN.