Treatment of CBA mice with cobra venom factor (CVF) decreased their C3 levels to less than 10 per cent of normal and resulted in a simultaneous increase of their susceptibility to intraperitonealE. coli06 infection. Animals immunized and treated with CVF had an infection resistance similar to untreated controls but considerably less than mice immunized only. The CVF treatment did not affect the antibody formation after immunization. Untreated or immunized AKR mice deficient in C5 did not show decreased resistance to the infection. Exposure of NMRI mice to preformed antigen‐antibody complexes unrelated to the infection did not increase the susceptibility of the animals to infection, neither did it impair their C3 levels. Two out of five freshly frosen (‐70°C) normal rabbit sera gave significant, heat‐labile protection of mice to theE coliinfection without containing any antibodies detectable with the ELISA. This protective capacity was not abolished with zymosan treatment affecting the levels of complement factors and could be »natural antibodies« stimulated from the environment. In testing whether similar protective factors as those found in normal rabbit serum could be raised in CBA mice, such animals were orally given killedE. coli06 bacteria. This did not affect the resistance to theE. coliinfection or to the rise of specific antibodies after immu