The onset of an acute phase response is one of the initial steps in the defense against an infectious organism. Alpha(2)-macroglobulin (alpha(2)M), an acute phase protein in most mammalian species, is known to have a broad antiprotease activity, but it can also bind a number of growth factors, cytokines, ions and lipid factors. We have shown that alpha(2)M-deficient (MAM-/-) mice are more resistant to a lethal Gram-negative infection compared to control mice. This increased resistance was reflected in significantly higher body temperatures, compared to control mice, during the infection as well as in a prolonged and increased survival. Moreover, the clearance of bacteria in MAM-/- mice was significantly more efficient than in control mice. On the other hand, MAM-/- mice were more susceptible to endotoxin. An LD(100) challenge with endotoxin in MAM-/- mice was not lethal for control mice. Our data suggest that alpha(2)M plays a dual role during an acute phase response. In the establishment of a lethal Gram-negative infection, leading to sepsis and septic shock, it has a mediating role by hampering the efficient clearance of bacteria. During endotoxic shock, however, alpha(2)M has a rather protective function.