Approximately 25% of polymorphonuclear leukocytes (PMNL) circulate in heterotypic complexes with one or more activated platelets. These platelet-neutrophil complexes (PNC) require platelet CD62P expression for their formation and represent activated subpopulations of both cell types. In this study, we have investigated the presence, time course, and mechanisms of PNC formation in 32 cases of severe pediatric meningococcal disease (MD) requiring intensive care. There were marked early increases in PMNL CD11b/CD18 expression and activation, and reduced CD62L expression compared with intensive care unit control cases. Minimal platelet expression of the active form of alphaIIbbeta3 (GpIIb/IIIa) was seen. PNC were reduced on presentation and fell to very low levels after 24 h. Immunostaining of skin biopsies demonstrated that PNC appear outside the circulation in MD. In vitro studies of anticoagulated whole blood inoculated with Neisseria meningitidis supported these clinical findings with marked increases in PMNL CD11b/CD18 expression and activation but no detectable changes in platelet-activated alphaIIbbeta3 or CD62P expression. In vitro PMNL activation with N. meningitidis (or other agonists) potentiated the formation of PNC in response to platelet activation with adenine diphosphate. Therefore, in severe MD, PMNL activation is likely to promote PNC formation, and we suggest that the reduced levels of PNC seen in established MD reflect rapid loss of PNC from the circulation rather than reduced formation.