Mice are susceptible to systemic infection with Francisella tularensis strain LVS; thus, the intraperitoneal (i.p.) lethal dose at 50% (LD50) in C3H/HeN and C57BI/6J mice is only a single bacterium, while the intradermal (i.d.) LD50 is more than 10(4). Here we show that the LD50 when LVS is introduced via the skin, either i.d. or subcutaneously (s.c.), ranges from 7 x 10(4) to 2 x 10(6). Sublethal i.d. or s.c. infection (priming) invariably leads to the generation of systemic and specific protective immunity: primed mice survive lethal i.p., intravenous (i.v.), or i.d. challenges of LVS but not Salmonella typhimurium W118 or Escherichia coli 018:K1:H7 strain BORT.