We tested whether genetically elevated levels of C-reactive protein (CRP) cause increased risk of ischemic heart disease and ischemic cerebrovascular disease. Levels of CRP >3mg/L, compared with levels <1mg/L, associated with a 1.6- and 1.3-fold increased risk of ischemic heart disease and ischemic cerebrovascular disease. Genotype combinations of the 4 CRP polymorphisms associated with up to a 64% increase in CRP levels, resulting in a theoretically predicted increased risk of up to 32% for ischemic heart disease and up to 25% for ischemic cerebrovascular disease. However, these genotype combinations did not associate with increased risk of ischemic heart and cerebrovascular disease.