The structure-activity relationship of 18-carbon fatty acids (C 18 FAs) on human neutrophil functions and their underlying mechanism were investigated. C 18 unsaturated (U)FAs potently inhibited superoxide anion production, elastase release, and Ca 21 mobilization at concentrations of UFAs did not reduce extracellular Ba 21 entry in FMLP-and thapsigargin-activated neutrophils. In summary, the inhibition of neutrophil functions by C 18 UFAs is attributed to the blockade of Ca 21 mobilization through modulation of PMCA. We also suggest that both the free carboxy group and the number of double bonds of the C 18 UFA structure are critical to providing the potent anti-inflammatory properties in human neutrophils.-Hwang,