The germ-line loss-of-function VHL R200W mutation is common in Chuvashia, Russia and occurs in other parts of the world. VHL R200W homozygotes have elevated hypoxia inducible factor (HIF)-1 and HIF-2 levels, increased hemoglobin concentration, propensity to thrombosis and early mortality. Because the mutation persists from an ancient origin, we hypothesized that there is a heterozygote advantage. Thirty-four VHL R200W heterozygotes and 44 controls over 35 years of age from Chuvashia, Russia were studied. Anemia was defined as hemoglobin less than 130 g/L in men and less than 120 g/L in women. Mild anemia was present in 15% of VHL R200W heterozygotes and 34% of controls without a mutated VHL allele. By multivariate logistic regression, the odds of anemia were reduced an estimated 5.6-fold in the VHL R200W heterozygotes compared to controls (95% confidence interval 1.4–22.7; P= 0.017). In conclusion, heterozygosity for VHL R200W may provide protection from anemia; such protection could explain the persistence of this mutation.