BACKGROUND & AIMS: Polyphenols exert a variety of biological properties, including antioxidant, immunomodulatory and antigenotoxic effects. In a randomized crossover study in healthy men, we investigated the effects of orange juice and its major polyphenolic compound hesperidin on a panel of immune cell functions, including cytokine secretion by leukocytes, lytic activity of NK cells, and the Reactive Oxygen Species (ROS) burst by polymorphonuclear neutrophil cells (PMN). METHODS: The protocol design was divided into three 4-week treatment periods separated by 3-week wash-out intervals, for total study duration of 18 weeks. During treatment periods, volunteers (n = 24) consumed daily 500 mL of orange juice, or an isocaloric control beverage with hesperidin (292 mg in a capsule), or of the same control beverage with a placebo. RESULTS: Whatever the intake was, no variations were recorded on leukocyte subset distributions (PMN, B and T lymphocytes, NK cells and monocytes), ROS production by stimulated PMNs, lytic activity of NK cells or cytokine production capacity of leukocytes in well-nourished healthy volunteers. CONCLUSIONS: We show that consumption within the usual daily intake range of orange juice and its major polyphenol hesperidin do not induce immunomodulation of cell immune function in healthy well-nourished humans.