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Omega-3 fatty acids, e.g., dokosahexaenoic acid (DHA) and eikosapentaenoic acid (EPA), ameliorate inflammatory reactions by various mechanisms, but the role of prostaglandins remains unclear. Our aim was to determine if dietary supplementation with a DHA-rich fish oil influenced the release of PGF2αfrom peripheral blood mononuclear cells (PBMC). In the OmegAD study, 174 Alzheimer disease patients received either 1.7 g DHA plus 0.6 g EPA or a placebo daily for six months. PBMCs from the 21 (9 on fish oil and 12 on placebo) first-randomized patients were stimulated with either lipopolysaccharide (LPS) or phytohemagglutinin (PHA) before and after 6 months. Our results showed that plasma concentrations of DHA and EPA increased significantly at 6 months in the omega-3 group. PGF2αrelease from LPS- (but not from PHA-) stimulated PBMC was significantly diminished in this group; no change was noted in the placebo group. PGF2αchanges correlated inversely with changes in plasma DHA and EPA. Decreased IL-6 and IL-1βlevels correlated with decreased PGF2αlevels. The stimulus-specific PGF2αrelease from PBMC after 6 months of oral supplementation with the DHA-rich fish oil might be one event related to reduced inflammatory reactions associated with omega-3 fatty acid intake.