Activation of polymorphonuclear leukocytes (PMN) plays an important role in vascular injury associated with systemic vasculitis and in models of autoantibody- and immune complex-mediated disease. The potential role of intravascular activation of PMN, however, is confounded by the observation that some stimuli injected i.v. (e.g., IL-8 and C5a) lead to L-selectin shedding by PMN, which inhibits attachment to endothelium and may be functionally anti-inflammatory. To explore the impact of Fcγ receptor (FcγR)-mediated activation on the PMN adhesive phenotype, FcγRIIa (CD32) and FcγRlllb (CD16) were targeted with receptor-specific reagents, and the expression of adhesion molecules-mediating rolling (L-selectin) and firm adhesion (CD11b/ CDT8) was measured. Engagement of either FcγRIIa or FcγRIIIb leads to activation, demonstrated by degranulation (up-regulation of CD66b), and to increased expression of total CD11b/CD18 and functional CD11b/CD18 (I-domain). In contrast, L-selectin shedding induced by PMN FcγR was divergent. Despite the 5- to 10-fold greater expression and engagement at saturation, activation via FcγRIIIb led to little or no change in L-selectin expression. Stimulation of PMN with intact murine anti-receptor IgG1 showed a contribution of FcγRIIa receptor polymorphisms, underscoring the direct influences of FcyR allotypes on receptor function. These observations suggest that FcγRIIIb-mediated activation of circulating PMN may lead to a proadhesive phenotype likely to promote systemic vascular damage. This FcγR-mediated adhesive phenotype will vary with the receptors engaged and their allotypes, which, in turn, reflect properties of the immune complex and the genetics of the host.