Cytomegalovirus (CMV) is a β-herpes virus common worldwide with prevalence of seropositivity reaching 80% in some parts of the USA. Primary infection is relatively benign for most infected individuals, after which the virus will persist lifelong in a latent state. However, CMV can cause severe effects in newborns in whom it is acquired congenitally, as well as immunocompromised individuals, including transplant recipients. CMV reactivation after allogeneic hematopoietic stem cell transplantation has been associated with increased transplant-related mortality and increased risk for graft-versus-host disease. Thus, understanding the role of immunogenetic variation in risk for CMV infection can provide insight into the immune control of this ubiquitous pathogen. Because of their central role in the immune response to pathogens, we hypothesized that variation in HLA genes may impact infection with CMV in healthy individuals. In this study, we examine HLA variation with respect to serostatus for CMV, using high-resolution HLA genotyping data from more than 500,000 individuals registered as donors with the NMDP and DKMS stem cell donor registries. The results of this research may provide a framework for understanding immunological conditions necessary for efficient viral control.