Neutrophils from patients with paroxysmal nocturnal hemoglobinuria (PNH) show a deficiency for the glycosylphosphatidylinositol- (GPI) linked Fc gamma receptor IIIb (Fc gamma RIIIb, CD16). The functional consequences of this defect are not clear. Here, we examined Fc gamma RIIIb-deficient neutrophils for their activation via Fc gamma receptors. Hydrogen peroxide (H2O2) production and change of intracellular free calcium [Ca2+]i were used as parameters for cell activation. Fc gamma RII and Fc gamma RIIIb stimulation was reached by cross-linking using fragments of monoclonal antibodies or incubation with monoclonal IgG cryoglobulin complexes. In parallel to the deficiency of Fc gamma RIIIb expression, H2O2 production and [Ca2+]i influx were decreased after cross-linking of Fc gamma RIIIb in PNH neutrophils compared with that for normal neutrophils. Stimulation via Fc gamma RII was not affected. Cryoglobulin complexes previously shown to activate normal neutrophils predominantly via Fc gamma RIIIb stimulated PNH neutrophils at a level not significantly weaker than controls. But this activation was mediated only via Fc gamma RII as shown by blocking studies. The results suggest that the loss of GPI- anchored Fc gamma RIIIb is functionally replaced by Fc gamma RII during the immune complex stimulation of PNH neutrophils. Therefore, the equipment of neutrophils with pleomorphic Fc gamma receptors prevents an immunodeficiency in PNH.