Abstract--Although markers of systemic inflammation may have a role in the development of hypertension, supportive clinical data remain limited. We, therefore, examined interleukin (IL)-6 and C-reactive protein (CRP) in a nested case-control study of 400 women developing hypertension and an equal number of age-matched normotensive control subjects during 10 years of follow-up as part of the Women’s Health Study. All of the women initially had nonhypertensive blood pressure values and no history of diagnosis or treatment. Subjects provided self-reported risk factors, and IL-6 and CRP were measured from baseline bloods. Case subjects reported elevated systolic (140 mm Hg) or diastolic (90 mm Hg) blood pressure, newly diagnosed hypertension, or initiating antihypertensive treatment during follow-up. In crude-matched models, IL-6 and CRP quartiles were each strongly associated with hypertension risk (both Ps for trend <0.0001). In multivariate models, the linear trends became nonsignificant, and the relative risks (95% CIs) of hypertension for IL-6 reduced to 1.00 (ref), 1.29 (0.76 to 2.19), 2.14 (1.23 to 3.73), and 1.70 (0.92 to 3.13) and for CRP were 1.00 (ref), 2.09 (1.16 to 3.76), 2.51 (1.42 to 4.44), and 2.44 (1.29 to 4.64), primarily because of confounding by body mass index. Simultaneous adjustment for IL-6 and CRP modestly attenuated both sets of relative risks, although more for IL-6. Finally, there was no effect modification by baseline blood pressure or other risk factors (all Ps for interaction >0.05). Therefore, after multivariate adjustment and strong confounding by body mass index, IL-6 was weakly associated and CRP strongly associated with hypertension risk. In models simultaneously examining IL-6 and CRP, only CRP remained strongly associated with an increased risk of hypertension.