AIM: To evaluate recent human studies with respect to the interpretation of whether elevated plasma levels of C-reactive protein (CRP) cause cardiovascular disease (CVD), or whether elevated CRP levels more likely is an innocent bystander. DATA SYNTHESIS: Elevated CRP concentrations are consistently associated with CVD risk. A recent study showed that aggressive statin treatment caused reductions of 50% in LDL cholesterol, 37% in CRP, 44% in CVD events, and 20% in total mortality, and that the highest treatment benefits were obtained in those with the lowest achieved levels of both LDL cholesterol and CRP. However, a reduction in CRP levels after statin treatment could be secondary to the reduced LDL cholesterol levels, and thereby less inflammation in atherosclerotic plaques. We recently performed 4 large Mendelian randomization studies, studies that demonstrated that elevated CRP associate with increased risk of CVD, that genetic variation in the CRP gene associate with increased CRP levels, but that this genetic variation in the CRP gene do not associate with increased risk of CVD. In contrast to previous studies, these new studies had enough statistical power to effectively exclude that genetically elevated CRP cause CVD. CONCLUSION: These data suggest that elevated CRP per se does not cause CVD; however, inflammation per se possibly contributes to CVD. Elevated CRP levels more likely is a marker for the extent of atherosclerosis or for the inflammatory activity and vulnerability of atherosclerotic plaques, and thus simply an innocent bystander in CVD.