Allogeneic, normal mouse tissues exerted a protective effect in C58 mice against lethal challenge with line lb leukemic cells. The factor responsible for protection was present in homogenates of spleen, lymph node, thymus, and liver of BALB/wm, DBA/2J, C3H/HeJ, and C57BL/6J strains. All these mice are negative for the Gross virus antigen (G−). A much lower degree of protection was found when similar tissue homogenates from the AKR, G + strain of mice were used, and no protection was exerted by syngeneic C58 tissue homogenates. The protective factor was found mainly in the mitochondrial-rich fraction when spleen cells from normal BALB/wm mice were fractionated, and was resistant to deoxyribonuclease and ribonuclease, but sensitive to heat and trypsin. Passive protection could be conferred by spleen cells removed from immune C58 mice and transferred to normal, syngeneic C58/wm mice. Protection occurred if C58/wm mice were challenged with lb cells as early as 30 minutes after injection of normal BALB/wm tissue homogenate, and persisted for several months, but it could not be induced in irradiated C58/wm mice. The data suggested that the protective effect was due to active immunization induced by an antigen on certain normal mouse tissues which cross-reacted with line lb leukemic cells.