Pycnogenol (PYC), an extract of French maritime pine bark (Pinus pinaster), is a potent antioxidant with potential health benefits. Its bioavailabilty has previously been shown by urinary excretion studies of constituents and metabolites of PYC. The aim of this study was to test the effect of PYC supplementation on measures of oxidative stress and the lipid profile in humans. Twenty-five healthy subjects received PYC (150 mg/d) for 6 wk. Fasting blood was collected at baseline, after 3 and 6 wk of supplementation, and again after a 4-wk washout period. After 6 wk of supplementation with PYC, a significant increase in plasma polyphenol levels was detectable, which was reversed after the 4-wk washout phase. The antioxidant effect of PYC was demonstrated by a significant increase in oxygen radical absorbance capacity (ORAC) in plasma throughout the supplementation period (P < 0.05). The ORAC value returned to baseline after the 4-wk washout period. Moreover, in addition to its antioxidant effects, PYC significantly reduced LDL-cholesterol levels and increased HDL-cholesterol levels in plasma of two-thirds of the subjects. While the LDL changes reversed during washout, the HDL increase did not. There was no significant difference in LDL oxidizability or plasma lipid peroxides following PYC supplementation. Hence, following oral supplementation in humans, PYC significantly increases antioxidant capacity of plasma, as determined by ORAC, and exerts favorable effects on the lipid profile.