alpha 2-Macroglobulin (alpha 2M) is converted from its native form into electrophoretically "fast" forms by reaction with proteinases or with methylamine. The "fast" forms both bind to specific receptors on macrophages (MP). We have previously shown that alpha 2M "fast" forms modulate effector functions of murine peritoneal MP. In the present study, alpha 2M "fast" forms antagonized the increase in MP HLA-DR and Ia expression induced in vitro by interferon-gamma (IFN-gamma). This effect was observed with human peritoneal MP, as well as MP from peptone-injected and bacillus Calmette-Guérin-infected mice of three strains. alpha 2M-trypsin, which had been reacted with aprotinin and alpha 2M-methylamine, both of which lack proteolytic activity, also antagonized interferon-induced Ia expression. alpha 2M "fast" forms also reduced the ability of MP to serve as accessory cells for lectin-induced lymphocyte proliferation. alpha 2M "fast" form is an immune modulator of human and murine MP function, probably through a specific receptor-mediated mechanism.