Our data establish that migration inhibition factor (MIF) and migration enhancement factor (MEF) mutually neutralize the effect of each other in a concentration-dependent manner. The monosaccharides L-fucose and D-mannose were also shown to reverse MIF and additionally to stimulate alveolar macrophage (AM) migration in the absence of MIF. The specific activity of these sugars was increased 200-fold when conjugated to bovine serum albumin (BSA). Macrophage activation is usually observed concurrently with migration inhibition when macrophages are incubated with MIF preparations. Migration inhibition occurred also when AM were incubated in the presence of known metabolic activators (MDP, PMA, and LPS). It was found that L-fucose, D-mannose, L-fucosyl BSA, and D-mannosyl BSA could reverse migration inhibition caused by MIF as well as by these metabolic activators. These observations suggest that reversal of MIF by L-fucose is unexplained solely on the basis that L-fucose is functioning as a competitive inhibitor; instead, they suggest that MEF and the above sugars and their conjugates stimulate AM through a receptor system different from the MIF receptor. These observations support the concept that MEF is an important macrophage modulator in CMI responses.