Previous studies attempting to influence the severity of collagen-induced arthritis (CIA) by modulating the LIGHT (lymphotoxin-related inducible ligand that competes for glycoprotein D binding to herpesvirus entry mediator (HVEM) on T cells)/lymphotoxin pathway have yielded conflicting results. To further clarify the role of LIGHT in autoimmune arthritis, a HVEM-Ig fusion protein was used. CIA was induced in DBA1 mice, which were injected i.p. with recombinant HVEM-Ig fusion protein and control Ig at different time points. Severity of clinical arthritis and histologic joint destruction were significantly increased in HVEM-Ig-treated mice compared with control-Ig-treated mice. Collagen II-induced in vitro T cell proliferation and IFN-gamma production was augmented in mice treated with HVEM-Ig, as was the production of IgG2a anti-collagen II Ab. Accordingly, serum concentrations of IFN-gamma and IL-6 were higher in mice treated with HVEM-Ig. In conclusion, HVEM-Ig aggravates autoimmunity in collagen-induced arthritis, which is possibly mediated by interaction with B and T lymphocyte attenuator (BTLA) or CD160, despite the blockade of LIGHT. Hence, HVEM-Ig seems not to be a valid therapeutic option in autoimmune arthritis.