BACKGROUND AND OBJECTIVES: It is well known that the higher the blood pressure, the greater the chance of cardiovascular disease, but the factors that are responsible for this association remain largely unknown. We sought to determine whether blood pressure, in a dose-dependent way, is associated with systemic inflammation, which is a known risk factor for cardiovascular events. SUBJECTS AND METHODS: We analyzed the data from 5,626 participants, aged 40-65 years, of the Third National Health and Nutrition Examination Survey (NHANES III). We quantified the blood pressure by dividing the participants into the normal, pre-, stage 1 and stage 2 hypertension groups based on the Joint National Committee 7 (JNC) classification. We used multiple linear and logistic regression models to determine the relationship between blood pressure and the levels of inflammatory markers. RESULTS: After adjustments were made for various co-morbidities, participants with stage 2 systolic hypertension had higher circulating leukocyte levels [840/microliter (95% confidence interval [CI], 374 to 939/microliter)] and fibrinogen levels [24.5 mg/dL (95% CI, 8.9 to 31.9 mg/dL)] than those participants with normal blood pressure. They also showed higher circulating C-reactive protein levels (C-reactive protein>10.0 mg/L: p for trend=0.001). There was a dose-dependent increase for the circulating levels of the risk factors across the different levels of systolic blood pressure, but not for diastolic blood pressure. CONCLUSION: These findings demonstrate that an elevated systolic blood pressure is an independent risk factor for systemic inflammation and this may explain why systolic hypertension is a risk factor for atherosclerosis and cardiovascular events.