C-reactive protein (CRP) is one of the most characteristic acute phase proteins which appear in the serum during certain inflammatory diseases. We report here that human CRP acquired the ability to augment platelet reactivity when treated with an Fe2+ (Cu2+)-ascorbate system. CRP modified by such treatment showed no appreciable activation of platelets in the absence of platelet activators such as platelet-activating factor, thrombin, or ADP. However, in the presence of the modified-CRP, irreversible activation of platelets occurred with sub-optimal doses of platelet-activating factor and other stimulatory agents for platelets. CRP without any treatment did not show any modulating activity. Each component of the Fe2+-ascorbate system was required for modification of CRP, suggesting that CRP was modified through an oxidative process. The modification of the CRP structure was confirmed by the change in the fluorescence spectrum of 8-anilino-1-naphthalene sulfonate complexed with CRP, the increased susceptibility of CRP to proteolytic enzymes and the altered reactivity to anti-CRP mAb. We also found an inactivating system for the modified CRP in plasma. The modified human CRP did not show any modulating activity toward rabbit platelets, suggesting that the activity is species specific.