Human antibody responses to latent membrane protein 1 (LMP1) in patients with Epstein-Barr virus (EBV)-related disease syndromes were analyzed in detail. Only by immunoblot analysis with purified recombinant LMP1 and by IFA on recombinant LMP1-expressing insect cells could human antibodies directed against LMP1 be detected. Low serum levels of LMP1-directed antibodies could be detected in 3 of 8 EBV-positive Hodgkin's disease patients, 3 of 40 nasopharyngeal carcinoma patients, 2 of 23 Burkitt's lymphoma patients, and 1 of 27 non-Burkitt's lymphoma patients. No LMP1-directed antibodies could be detected in healthy EBV carriers, infectious mononucleosis patients, or patients with chronic EBV disease. All sera contained significant levels of EBV antibodies directed against the immunodominant EBV proteins and peptides. From this study, it can be concluded that LMP1 is a protein with a very low immunogenicity for the humoral immune response in humans.