An intervention trial designed to lower the amount of fat in the diet was conducted to test the effect of reduced fat consumption (LF diet) on activity of natural killer (NK) cells in humans. Of 26 men enrolled initially, 17 successfully completed the intervention and lowered their fat intake to less than 30% of calories as fat. Data were analyzed in two ways. The paired t test showed a marked increase in NK-cell activity from baseline to the end of the LF-diet intervention (t = 4.77, p = 0.0002). Results of a general linear model showed an effect of lowering total dietary fat on increased NK-cell activity (approximately 0.53% increase for each absolute percent of calories as fat, p = 0.14) for all men and a highly significant effect in a subset of men who ate greater than 25% of calories as fat at baseline (approximately 1.22% increase, p = 0.009). These results were obtained after changes in total caloric intake, weight, exercise, and other fat-related covariates were accounted for.