The relationship between the development of acute hepatitis and the production of TNF‐α IFN‐γ and IL‐6 by liver‐associated T lymphocytes following intravenous injection of concanavalin A (Con A) was studied in rats. Following a single injection of Con A, there was a dose and time‐dependent correlation in the serum levels of serum alanine aminotransferase (ALT), IL‐6, IFN‐γ and TNF‐α. These increases correlated with an increase in the numbers of CD4⁺, CD8⁺ and CD25⁺ T cells in blood and CD4⁺ and CD25⁺ T cells in the liver perfusate, but not with CD8⁺ T cells in liver perfusate. Increased levels of IL‐6, IFN‐γ and TNF‐α were constitutively produced by liver‐associated CD4⁺ T cells when cultured. In Con A‐stimulated cultures, liver‐associated CD4⁺ T cells secreted increasing levels of TNF‐α in a time‐dependent manner following Con A injection, but TNF‐α production by peripheral blood lymphocytes was transient with peak levels detected at 1 h which then declined over 24 h. Histological examination of the liver revealed fatty change, hepatocyte degeneration and necrosis, with an associated cell infiltrate of neutrophils and CD4⁺ T cells both in the portal areas and around the central veins. These results support the hypothesis that Con A‐induced liver damage is mediated by CD4⁺ T cells acting within the liver, at least in part through the secretion of TNF‐α, IFN‐γ and IL‐6.