The cooperation between IFN-α/β and FL, the ligand of Fms-like tyrosine kinase 3 (Flt3), plays an important role in the defense against herpes simplex virus type 1 (HSV-1) in neonates. Treatment of neonatal mice with recombinant IFN-α has a short-term, FL-independent and a long-term, FL-dependent protective effect against HSV-1. In mice lacking FL, neonatal resistance against HSV-1 is very low and DC numbers in the spleen are reduced. The treatment of these mice with rIFN-α at day 6 resulted in an increased resistance against infection with HSV-1 at day 7. In C57BL/6 mice, treatment with rIFN-α at birth induced both FL and plasmacytoid DC (pDC), resulting in enhanced resistance against HSV-1 at day 7. In contrast, in mice lacking FL, IFN-α treatment at birth did not influence the splenic cell composition and had no effect on viral protection. The transfer of pDC to mice lacking FL enhanced viral resistance. Therefore, the induction and function of pDC, normally controlled by IFN-α/β and FL, are decisive for viral resistance in neonatal mice.