Hyperhomocysteinemia is a risk factor for cardiovascular disease in the general population, but in end-stage renal disease patients some studies show a reverse association, i.e. higher levels of homocysteine are associated with better clinical outcome. In this brief review, we review the evidence that malnutrition, hypoalbuminemia, inflammation and diabetes mellitus may lower circulating levels of homocysteine. As these factors are strong predictors of clinical outcome, this may explain why lower homocysteine levels in end-stage renal disease patients are associated with worse clinical outcome. We conclude that these factors need to be taken into account in multivariate models evaluating the impact of hyperhomocysteinemia as a risk factor in end-stage renal disease patients.