The protein array described here provided a highly sensitive platform. Plasma with EBNA1 titers between 1:80 and 1:320 in conventional anticomplement immunofluorescence assays had titers of 1:10,000 or greater in the array assay (data not shown). The assay showed specificity. IgG responses to KSHV proteins were detected in sera from HIV-positive individuals with a diagnosis of KS or lymphoma but were not detected in a panel of HIV-negative lymphoma patients or healthy normals. This result, along with comparisons between EBV and KSHV responses in the HIV-positive samples, indicates that cross-reactivity between homologous proteins encoded by EBV and KSHV was not a confounding factor. This array provides a new platform for investigating the contribution of humoral immune responses in patients with EBV-and KSHV-associated pathologies.