Deactivation is a phenomenon in which leucocytes exposed in vitro to a chemotactic factor in the absence of a concentration gradient are rendered relatively unresponsive to stimulation by a subsequent chemotactic gradient. In patients with idiopathic cold-induced urticaria, the elicitation of a local experimental angioedematous lesion causes the release of two chemotactic principles previously shown to deactivate leucocytes in vitro, high molecular weight neutrophil chemotactic factor (HMW-NCF) and eosinophil chemotactic factor of anaphylaxis (ECF-A), into the venous circulation draining the challenged extremity. However, biopsy specimens of lesional skin sites obtained for up to 24 hr show no infiltration of cells. For this reason, the in vitro chemotactic responsiveness of neutrophils to the chemotactic factor HMW-NCF and C5 fragments were assessed in three patients at various times after experimental challenge. Leucocytes from venous effluent draining an experimentally-induced angioedematous lesion were markedly impaired in their chemotactic responsiveness to both chemotactic factors 5 min after challenge, while cells taken from an unchallenged extremity at the same time responded normally. Cells from both arms were equally impaired in their responsiveness 1 hr later, thereby demonstrating that the chemotactic defect becomes systemic. The acquired defect was dissipated 4 hr after challenge. These data suggest that deactivation may occur in vivo and may alter host responsiveness in states where chemotactic factors are released into the circulation.