Summary. Antibody-mediated platelet destruction is a poorly understood process, although several lines of evidence suggest that Fcγ receptor (FcγR)-expressing splenic macrophages may be involved. In this study, chemiluminescence (CL) was used to measure the in vitro metabolic response of human monocytes to platelets sensitized with a human immunoglobulin (Ig)G1 recombinant antihuman platelet antigen-1a (anti-HPA-1a) antibody (B2G1; P-hrIgG1). CL responses were inhibited, but not abrogated, in the presence of 10 µg/ml human IgG or murine IgG2a, suggesting that FcγRI was principally involved. Experiments to determine the effect of Fab fragments to FcγRII found that CL responses to P-hrIgG1 were significantly enhanced, indicating that crosslinking of monocyte FcγRII by platelet-bound hIgG may modulate concomitant activation by FcγRI. Several observations suggested that the CL responses to P-IgG were dependent on the activation of resting platelets during their co-culture with monocytes and their subsequent P-selectin-mediated adhesion. First, the magnitude of the CL response was related to the level of P-selectin expression following platelet activation with α-thrombin. Second, CL responses were inhibited in the presence of antibodies that block the binding of P-selectin to P-selectin glycoprotein ligand-1 but not when platelets were pretreated and then washed. Third, the addition of anti-HPA-1a to monocytes from HPA-1a-negative donors preincubated with HPA-1a-positive platelets resulted in rapid CL responses. Finally, PGI2 inhibited the CL response to resting P-hrIgG1. Thus, evidence is presented that the interaction of human monocytes with P-hrIgG1 is mediated by FcγRI, modulated via FcγRII, and enhanced by the presence of P-selectin on the platelet membrane.