Calorie restriction (CR) enhances immune response and prolongs life span in animals. However, information on the applicability of these results to humans is limited. T-cell function declines with age. We examined effects of CR on T-cell function in humans. Forty-six overweight, nonobese participants aged 20-42 years were randomly assigned to 30% or 10% CR group for 6 months. Delayed-type hypersensitivity (DTH), T-cell proliferation (TP), and prostaglandin E(2) (PGE(2)) productions were determined before and after CR. DTH and TP to T-cell mitogens were increased in both groups over baseline (p < or = .019). However, number of positive responses to DTH antigens (p = .016) and TP to anti-CD3 reached statistical significance only after 30% CR (p = .001). Lipopolysaccharide-stimulated PGE(2) was reduced in both groups but reached statistical significance after 30% CR (p < or = .029). These results, for the first time, show that 6-month CR in humans improves T-cell function.