The results of the experiments reported here reveal unique compartmental innate cytokine responses, with IFN-␣ and IFN-␤ production and NK cell IFN-␥ expression detected at 24 h after infection and peaking at 30 h after infection. Studies under conditions of blocked type 1 IFN receptor access and/or deficiency in STAT4 conclusively demonstrated that NK cell IFN-␥ expression was dependent on the type 1 IFNs and STAT4. The pathway enhanced the antiviral state. Interestingly, in comparison to other peritoneal populations, STAT1 induction in NK cells was delayed and separated from the NK cell IFN-␥ response by 10 to 12 h. Thus, the results uncover a key role for type 1 IFN activation of NK cell IFN-␥ and mechanistically resolve important issues concerning the earliest pathways to, sources of, and functions for IFN-␥.