Fc gammaRIIIb is a glycosylphosphatidylinositol(GPI)-anchored, low-affinity IgG receptor, expressed exclusively on human neutrophils. Upon activation or apoptosis of neutrophils, Fc gammaRIIIb is shed from the cell surface, but the enzyme(s) responsible for this process is (are) still unknown. Recently, metalloproteases have been suggested to mediate the shedding of cell surface proteins such as L-selectin and TNF-alpha. Using hydroxamic acid-based inhibitors of this class of proteases (BB-3103, Ro31-9790), we have observed a clear inhibitory effect on Fc gammaRIIIb shedding after PMA stimulation of neutrophils or induction of apoptosis. These inhibitors did not affect PMA-induced degranulation or superoxide generation.