Normal BALB/cByJ mice given a sublethal infection of Francisella tularensis strain LVS survived 10(6) LD50s of lethal challenge given only 3 days later. Here, we determine the cell types responsible for this very strong early protective immunity. Early protection is observed in athymic nu/nu mice but not fully immunodeficient scid mice, implicating a lymphocyte in this response. Using scid mice that are reconstituted with various purified cell subpopulations, as well as mice with genetically targeted disruptions in lymphocyte subpopulations (knockout mice), we demonstrate that strong early protection is highly dependent on B cells. This protective mechanism, which limits bacterial growth in the organs of the reticuloendothelial system very quickly after infection, requires IFN-gamma but is unlikely to involve specific Ab.