The response of guinea pig macrophages to migration inhibitory factor (MIF) is altered by several chemical treatments. Treatment of macrophages with the diazonium salt of sulfanilic acid (5 x 10(-6) to 4 x 10(-4) M) significantly increases the response of these cells to MIF. Treatment with acetic anhydride also augments the response of these cells to MIF. The latter finding suggests that alteration of amino, hydroxyl, or sulfhydryl groups is involved in this phenomenon. Treatment of macrophages with sodium periodate (2 x 10(-5) to 10(-3) M) which is known to oxidize cis-glycols and with hydroxylamine (2 x 10(-5) to 2 x 10(-3) M), which reacts with carbonyl groups also increases response to MIF. The following experiments suggest that the significant alteration occurs at the level of the cell surface. Incubation of macrophages with the diazonium salt of sulfanilic acid at 4 degrees C, at which temperature pinocytosis is largely inhibited, is sufficient to increase the MIF response. The activity of the cytoplasmic enzyme aspartate aminotransferase, which in homogenates is susceptible to inactivation by low concentrations of the diazonium salt of sulfanilic acid, is not decreased when intact macrophages are incubated with high concentrations of the diazonium salt of sulfanilic acid. Cumulatively, these findings suggest that modification of different functional groups on the macrophage surface causes the same physiologic effect.