Stimulation of human neutrophils with zymosan particles resulted in a dose-response release of IL-8 in the 24 h culture supernatant, measured using a specific radioimmunoassay. IL-8 was detected after 8 h (0.11±0.08 nM) and peaked at 24 h (2.81±0.85 nM). Two distinct PAF receptor antagonists, WEB 2086 and UK 74505 produced a dose-dependent inhibition of zymosan-induced IL-8 release. This inhibitory action was maximal (68% 10−6 M WEB 2086; 71% 10−8 M UK 74505) when the drug was co-administered with zymosan, becoming progressively less effective when administered at increasing intervals after addition of zymosan. In contrast, a specific LTB4 antagonist, LY 255283, an IL-1 receptor antagonist and an anti-human TNFα antibody were unable to modulate the response indicating that these mediators are not involved. This study provides the first direct evidence of a central role for the phospholipid mediator PAF in the pathway of IL-8 release, following neutrophil activation by a particulate stimulusin vitro.