The antitumor activity of ascorbic acid has been reported by different investigators. In this study, we determined the in vivo effects of ascorbic acid and its modified formulation (Ultra Potent-C) on human natural killer (NK) cell activity. Twenty-two healthy subjects were given either ascorbic acid or Ultra Potent-C orally at a concentration of 60 mg kg-1. Vitamin C uptake was measured in the plasma and by peripheral blood lymphocytes (PBLs). The uptake of vitamin C by PBLs was maximized at 2-4 h and was maintained at a high level up to 24 h. At the maximal point the uptake of Ultra Potent-C was higher by 18-25% than plain ascorbic acid. In addition, PBL-NK activity was measured by a 4-h 51Cr release assay using K562 as targets. The results demonstrated that ascorbic acid has a biphasic pattern of NK function; an early transient depression in NK activity (29%) at 1-4 h that is subsequently followed by a significant enhancement (200-400%) between 8 and 24 hours. However, the pattern of NK activity in the Ultra Potent-C group was different from the ascorbic acid group and the early transient depression in NK activity was not observed. We conclude that ascorbic acid or its modified form is a potent immunomodulator.