Activation of the neutrophil NADPH oxidase by either the bacterial peptide fMLP or phorbol myristate acetate (PMA) is partially suppressed by SB 203580, a specific inhibitor of the MAP kinase family member, SAPK2/p38. The concentration of SB 203580 that suppresses activation of NADPH oxidase is similar to that which inhibits SAPK2/p38 in vitro, and both fMLP and PMA induce an extremely rapid and potent activation of SAPK2/p38 in neutrophils. SB 203580 does not exert its effect by preventing the neutrophil priming reaction, by suppressing the phosphorylation of p47phax, or by preventing the translocation of p47phax/p67phax to the plasma membrane.