Red cell distribution width (RDW) is linked to cardiovascular risk in the general population, an association that might be driven by inflammation. Whether this relationship holds for patients with Human Immunodeficiency Virus (HIV) infection has not been previously studied. Using a large clinical registry, we show that elevated RDW (>14.5%) is independently associated with increased risk of coronary artery disease (odds ratio (OR) 1.39 [1.25–1.55]), peripheral vascular disease (OR 1.41 [1.29–1.53]), myocardial infarction (1.43 [1.25–1.63]), heart failure (OR 2.23 [1.99–2.49]), and atrial fibrillation (OR 1.96 [1.64–2.33]). In conclusion, in the context of the inflammatory milieu that accompanies HIV infection, RDW remains a powerful marker of CV disease.