Purpose: Body mass index (BMI) is an important risk factor for clear-cell renal cancer (cc-RCC). A common molecular alteration in cc-RCC is loss-of-function of the von Hippel-Lindau (VHL) gene. We evaluated the association between BMI and VHL mutations in cc-RCC by using data from the Netherlands Cohort Study (NLCS), a prospective study, which comprises 120,852 persons. Methods: After 11.3 years of follow-up, 337 incident RCC cases were identified; 185 cc-RCC cases were included for analyses. Results: A high BMI at baseline was associated with an increased risk of cc-RCC with or without VHL mutations (per 1 kg/m<sup>2</sup>: hazard ratio [HR] = 1.09, 95% confidence interval [CI]: 1.02-1.16 and HR = 1.08, 95%CI: 1.01-1.15, respectively). BMI at age 20 was only associated with an increased risk of cc-RCC with VHL mutations (per 1 kg/m<sup>2</sup>: HR =1.09, 95% CI: 1.03-1.16). In contrast, BMI gain since age 20 was only associated with an increased risk in VHL wild-type cases (per 1 kg/m<sup>2</sup>: HR = 1.10, 95% CI: 1.03-1.19). Conclusion: Our findings indicate that BMI may be differently associated with subtypes of RCC based on VHL mutations. © 2010 Elsevier Inc.