The studies of dietary fish oil supplementation in healthy volunteers demonstrate a significant increase in neutrophil EPA content, a concomitant reduction in neutrophil AA content, and suppression of neutrophil LTB4 synthesis by supplementation with dietary fish oil containing approximately 3-4 g EPA daily for a minimum of 4 weeks. Suppression of neutrophil chemotactic responsiveness to LTB4 and FMLP was observed after dietary n-3 PUFA supplementation at these levels. Dietary EPA is more active than DHA in eliciting these effects in human neutrophils. Dietary n-3 PUFA supplementation inhibits neutrophil chemotaxis to these ligands through the inhibition of the signal transduction pathway between the receptor and phospholipase C, as demonstrated by the inhibition of chemotaxin-stimulated IP3 formation, in the absence of an effect on the number or affinity of the respective chemotaxin receptors. In patients with RA, dietary supplementation with n-3 PUFA resulted in decreased AA content of cellular lipids, with an augmented EPA content and decreased LTB4 generation by neutrophils. Dietary supplementation with n-3 PUFA also resulted in augmentation of depressed neutrophil chemotaxis to LTB4 and FMLP. Preliminary findings suggest that the decreased responsiveness to chemotaxins of neutrophils from RA patients is due to down-regulation of chemotaxin receptor number, resulting in decreased signaling via chemotaxin receptors. Dietary fish oil PUFA partially reversed the down-regulation of the chemotaxin receptor of neutrophils of RA patients, but had a lesser effect on chemotaxin receptor signaling and function, probably due to a post-receptor inhibition induced by fish oil PUFA, as was previously observed in healthy controls. Several small clinical trials have each suggested that dietary supplementation with n-3 PUFA resulted in modest improvements in disease activity. Meta-analysis of these studies confirms statistically significant improvements in tender joint count and morning stiffness after 3 months of dietary fish oil supplementation in patients with RA. Dietary supplementation with gamma-linolenic acid-rich oils also inhibits neutrophil LTB4 formation, has other anti-inflammatory and immunosuppressive effects, and shows promise of therapeutic efficacy in RA.