Human herpesvirus 8 (HHV-8) is closely associated with Kaposi's sarcoma (KS), HIV-associated Castleman's disease, and primary effusion lymphoma. As a high frequency of non-Hodgkin's lymphoma (NHL) has been reported in patients with HIV-associated KS, we hypothesized that HHV-8 infection could be indirectly implicated in the pathogenesis of NHL. We assessed the prevalence of HHV-8 antibodies in 63 patients with NHL compared with 126 HIV-infected matched control patients without NHL. Serum samples from cases and controls were assayed for antibodies to HHV-8 lytic and latent antigens using an indirect immunofluorescence assay. In patients with concordant serologic results, HHV-8 antibodies were detected in 41.5% of the NHL cases and 37% of the controls. This absence of a significant difference in HHV-8 seroprevalence between cases and controls (p =.73) does not support a possible role for HHV-8 infection in the development of NHL in HIV-infected patients.