BACKGROUND: 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. We aimed to assess the association of total bilirubin with future hypertension risk and supplemented this with a Mendelian randomization approach to investigate any causal relevance to the association. METHODS AND RESULTS: Plasma total bilirubin levels were measured at baseline in the PREVEND (Prevention of Renal and Vascular End-Stage Disease) prospective study of 3989 men and women without hypertension. Hazard ratios (95% confidence intervals) of total bilirubin with incident hypertension were assessed. New-onset hypertension was recorded in 1206 participants during a median follow-up of 10.7 years. Baseline total bilirubin was approximately log-linearly associated with hypertension risk. Age- and sex-adjusted hazard ratio for hypertension per 1-SD increase in loge total bilirubin was 0.86 (0.81-0.92; P<0.001), which was attenuated to 0.94 (0.88-0.99; P=0.040) after further adjustment for established risk factors and other potential confounders. The association was marginally significant on further adjustment for high-sensitivity C-reactive protein (0.94; 0.88-1.00; P=0.067). A genetic variant at the UGT1A1*28 locus consistently shown to be strongly associated with circulating bilirubin levels-rs6742078-was not significantly associated with blood pressure or hypertension (P>0.05 for all), arguing against a strong causal association of circulating bilirubin with blood pressure. CONCLUSIONS: The weak and inverse association of circulating total bilirubin with future hypertension risk may be driven by biases such as unmeasured confounding and/or reverse causation. Further evaluation is warranted.