To test the hypothesis that fish oil supplementation can inhibit the expression of functionally associated molecules on the surface of human blood monocytes, we randomly assigned 12 healthy adults to receive either an n-3 polyunsaturated fatty acid-rich fish oil supplement for 21 d or to receive no supplement. The percentage of monocytes expressing major histocompatibility complex (MHC) class II molecules (HLA-DR, -DP, and -DQ), intercellular adhesion molecule-1, and leukocyte-function-associated antigen-1, and the intensity of expression of each molecule were quantified before and after the study period. Monocytes were examined immediately after blood sampling and again after incubation in serum-free culture medium for 24 h in the presence of interferon-gamma to up-regulate expression of MHC class II molecules by the monocytes. The intensity of expression of all the monocyte surface molecules examined was significantly reduced after fish oil supplementation (P < 0.025), although there was no change in the percentage of monocytes expressing each molecule. After incubation with interferon-gamma, there was a similar inhibition of surface molecule expression (with the exception of HLA-DQ) by monocytes from the fish oil-supplemented group, and there was a reduction in the percentage of monocytes expressing both HLA-DR and -DP molecules (P < 0.025). No significant changes were observed in the reference group. Dietary supplementation with fish oil can inhibit the expression of surface molecules involved in the function of human antigen-presenting cells, a potential mechanism by which n-3 fatty acids may suppress cell-mediated immune responses.