Aim To observe the effect of grape seed proanthocyanidin extract (GSPE) on serum C-reactive protein (CRP) in rabbits. Methods 15 New Zealand male rabbits were randomized into three groups with 5 rabbits in each group. The control group was fed with standard diet. The cholesterol group was fed with standard diet containing 1% cholesterol. The GSPE group was fed with standard diet containing 1% GSPE plus 1% cholesterol. All the rabbits were fed for twelve weeks. Blood samples were drawn from ear middle arteries of rabbits just before the experiment and at the first, the second, the forth, the eighth and the twelfth weekend of the experiment. All the rabbits were fasted for at least eight hours before the blood was drawn. Serum CRP was determined using a commercially available CRP EIA kit. All the rabbits were sacrificed at the twelfth weekend and aortas of the rabbits were excised for the morphological observation. Aorta samples were observed through optical microscope. Results Compared with the cholesterol group, the serum CRP contents were lowered markedly by dietary GSPE (p<0.001) at the first weekend and lasted to the end of the experiment. Both the cholesterol group and the GSPE group showed high correlation of the treat and time (r=0.99047, p<0.001 and r=0.74777, p<0.001). The extent and severity of atherosclerosis (the thick of aortas and the number of foam cells) of the GSPE group were less than those of the cholesterol group (p<0.01). Conclusions GSPE had the efficacy of anti-atherogenesis, one mechanism of which was that it can inhibit the CRP.