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.