Introduction: Circulating total bilirubin is known to be inversely and independently associated with future risk of cardiovascular disease. However, the relationship of circulating total bilirubin with incident hypertension is uncertain. Objective: We aimed to assess the association of total bilirubin with future hypertension risk. However, data on the relationship between bilirubin and blood pressure are scarce and inconclusive. Methods: We analysed data with a 50 minimal sufficient adjustment set of variables (MSAS) needed to estimate the unconfounded effect of bilirubin on blood pressure and hypertension (systolic/diastolic blood pressure __ampersandsignge;140/90 mmHg or using antihypertensive medication) was identified using the back-door criterion and included in all regression models. Results: In this prospective study, after adjustment for the MSAS variables, systolic blood pressure decreased progressively up to -2.5 mm Hg (p __ampersandsignlt; 0.001) and the prevalence of hypertension was up to 25% lower (P __ampersandsignlt; 0.001) in those with bilirubin __ampersandsignge;1.0 mg/ dl-the highest two deciles-compared with those with 0.1-0.4 mg/dl-the lowest decile. Sensitivity analyses showed these results were unlikely to be explained by residual confounding or selection bias. Conclusion: High serum bilirubin may decrease the risk of hypertension by inactivating and inhibiting the synthesis of reactive oxygen species in vascular cells. Strategies to boost the bioavailability of circulating and tissue bilirubin or to mimic bilirubin__ampersandsignrsquo;s antioxidant properties could have a significant impact on prevention and control of hypertension as well as coronary heart disease.