Immunomodulatory effects of endogenous and exogenous cannabinoids have been investigated in numerous studies, mostly performed with isolated cells or transformed cell lines, but only sparse data exist on human polymorphonuclear neutrophils (PMNs). We therefore investigated the respiratory burst reaction of human whole-blood PMNs under the influence of cannabinoids using flow cytometry. In their natural whole-blood milieu, a CB(2) receptor-dependent stimulation of the PMN respiratory burst was found at nanomolar concentrations of CP55 940 [(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol] and methanandamide after a 3-h incubation period, whereas the short-living and rapidly hydrolyzed endogenous ligand anandamide did not alter the burst reaction of whole-blood PMNs under the same experimental conditions. The stimulatory cannabinoid effect was totally absent in isolated PMNs but could be transferred onto isolated PMNs by adding the cell-free low-molecular mass plasma fraction (<5000 Da) of cannabinoid-incubated blood, indicating an indirect mechanism depending on humoral products or mediators. Results of our further experiments suggest that products of the arachidonic acid metabolism are mediators of the cannabinoid-induced enhancement of the respiratory burst reaction of whole-blood PMNs.