Objectives Fulminant viral hepatitis (FH) remains a serious clinical problem for which the underlying pathogenesis remains unclear. The B and T lymphocyte attenuator (BTLA) is an immunoglobulin-domain-containing protein that has the capacity to maintain peripheral tolerance and limit immunopathological damage during immune responses. However, its precise role in FH has yet to be investigated. Design BTLA-deficient (BTLA(-/-)) mice and their wild-type littermates were infected with murine hepatitis virus strain-3 (MHV-3), and the levels of tissue damage, cell apoptosis, serum liver enzymes, fibrinogen-like protein 2 (FGL2) and cytokine production were measured and compared. Survival rate was studied after MHV-3 infection with or without adoptive transferring macrophages. Results FGL2 production, liver and spleen damage, and mortality were significantly reduced in BTLA(-/-) mice infected with MHV-3. This effect is due to rapid, TRAIL (TNF-related apoptosis-inducing ligand)-dependent apoptosis of MHV-3-infected macrophages in BTLA(-/-) mice. The early loss of macrophages resulted in reduced pathogenic tumour necrosis factor (TNF) and FGL2 levels and lower viral titres. The importance of TNF in MHV-3-induced pathology was demonstrated by increased mortality in TNF-treated MHV-3-infected BTLA(-/-) mice, whereas TNF-/- mice were resistant to the infection. Moreover, adoptively transferring macrophages to BTLA(-/-) mice caused sensitisation, whereas blocking BTLA protected wild-type mice from virus-induced FH mortality. Conclusions BTLA promotes the pathogenesis of virus-induced FH by enhancing macrophage viability and function. Targeting BTLA may be a novel strategy for the treatment of FH.