We studied the in vitro production of interleukin-2 in nine healthy volunteers who added 18 g/day of fish-oil concentrate rich in n-3 polyunsaturated fatty acids to their normal Western diet for a period of 6 weeks. Interleukin-2 synthesis from stimulated peripheral blood mononuclear cells was suppressed from 6.2 ng/ml at baseline to 2.2 ng/ml 10 weeks after the end of n-3 fatty acid supplementation (65% decrease; P = .04). At the same time phytohemagglutinin-induced proliferation of mononuclear cells was suppressed by 70% from the presupplement level. Interleukin-2 production returned to the premedication level at the end of the studies. The results suggest that the effect of dietary n-3 fatty acids in some diseases may be mediated in part by decreased production of interleukin-2 and decreased mononuclear cell proliferation.