Kaposi sarcoma-associated herpesvirus (KSHV) has been identified as the etiologic agent of Kaposi sarcoma (KS). Although KSHV is required for the development of KS, immune dysfunction is a common and important cofactor in the development of KS, as illustrated by the presence of KS in association with HIV infection or immunosuppressive-drug treatment after transplantation. Because neutralizing antibodies (NAb) constitute an important component of an antiviral immune response, we examined the functionality of the humoral immune response associated with KS, by measuring KSHV NAb titers in 3 groups of subjects. Group 1 included subjects who were KSHV positive, KS positive, and human immunodeficiency virus (HIV) positive; group 2 included subjects who were KSHV positive, KS negative, and HIV positive; and group 3 included subjects who were KSHV positive, KS negative, and HIV negative. NAb titers were significantly lower among subjects with KS, compared with subjects who were infected with KSHV but who did not have clinical evidence of KS, in a multivariate model adjusted for HIV infection and CD4 T cell count. The data from the present study suggest that NAb may play a role in the control of KSHV infection and the prevention of progression of KSHV infection to KS.