Objectives: Hypertension and/or antihypertensive medication are reported to be risk factors of renal cell carcinoma (RCC). We investigated whether these risk factors are associated with von Hippel-Lindau gene (VHL) mutations in RCC. Methods: The Netherlands Cohort Study on Diet and Cancer (NLCS) started in 1986 (n = 120 852 men and women) and uses the case-cohort methodology. After 11.3 years of follow-up, 337 RCC cases and 4774 subcohort members were available for analysis. DNA was isolated from paraffin-embedded tumour tissue for VHL analysis. Results: Cohort members who reported hypertension or use of antihypertensive medication had a slightly (non-significant) increased risk of RCC: rate ratios (RR) 1.22 [95% confidence interval (Cl), 0.94-1.58] and 1.14 (95% Cl, 0.85-1.52), respectively. RRs were adjusted for sex, age, body mass index (BMI) and cigarette smoking. Of the 235 patients for whom tumour tissue specimens were collected, 187 had a clear-cell RCC, of whom 114 had a VHL mutation. History of hypertension was associated with a non-significantly increased risk of clear-cell RCC with VHL mutations: RR = 1.34 (95% Cl, 0.87-2.07), and was not associated with the risk of clear-cell RCC without VHL mutations; RR = 0.88 (95% Cl, 0.51-1.53). Use of diuretics was associated with clear-cell RCC without VHL mutations; RR = 2.11 (95% Cl, 1.16-3.83). Conclusions: In this study non-significantly increased risks for history of hypertension and use of antihypertensive medication with RCC were observed. The association with hypertension was stronger in RCC patients with VHL mutations, while there was a positive association of diuretics use and risk of RCC without VHL mutations. © 2005 Lippincott Williams & Wilkins.