In murine cutaneous leishmaniasis caused byLeishmania major(Lm), resistance often associates with the outgrowth ofLm-specific Th1 cells. Parasites are eliminated by Th1-mediated activation of infected macrophages (MØ) which destroyLmby producing toxic nitrogen and oxygen radicals. The cytokine IFN-α activates microbicidal functions of MØs and facilitates outgrowth of Th1 cells. Therefore, we compared the course of infection withLmin resistant C57BL/6 mice, bearing theIf-1 h high expression allele for IFN-α/β, with the congenic B6.C-H-28 c mouse, bearing theIf-1 l low expression allele from theLm-susceptible BALB/c strain. We observed that B6.C-H-28 c animals developed up to 70% larger footpad lesions and harbored up to 1000-fold more parasites than C57BL/6 mice. Furthermore, peakLm-specific IFN-γ production in the B6.C-H-28 c animals was lower and delayed by ≈2 weeks, whereas IL-4 production was higher and persisted ≈2 weeks longer. Since these results suggested that IFN-α/β plays a protective role in mice infected withLm,we determined whether infusing B6.C-H-28 c mice with IFN-α would influence the course of infection withLm.Unfortunately, the mice developed severe peritoneal hemorrhaging in response to injection with IFN-α. Therefore, we examined the ability of IFN-α to activate MØs to destroyLm in vitro. We observed that rIFN-α could synergize with subactivating doses of LPS to activate both C57BL/6 and BALB/c peritoneal MØs to produce NO and to kill intracellularLm.Taken as a whole, these results suggest that type I interferons may play a protective role in cutaneous leishmaniasis.