Activation of hepatic macrophages and systemic immunoparesis are prominent features of acute liver failure (ALF). However, the specific mechanism linking macrophage-associated inflammation and immunoparesis remains to be elucidated. The present study investigated the functional status and fate of hepatic macrophages, as well as their association with immunoparesis in ALF. Intravenous injection of concanavalin A (con A) was administered to develop a mouse model of ALF. Flow cytometry was performed to determine toll-like receptor 4 (TLR4) expression and the apoptotic rates of isolated hepatic macrophages in mice exposed to con A. The levels of TNF-α, IL-6 and IL-12p40 in serum and cell cultures were determined with enzyme-linked immunosorbent assay. TLR4 peak expression in hepatic macrophages was observed at ~0.5 h following exposure to con A and rapidly decreased at 1-3 h. The apoptotic rates of hepatic macrophages increased significantly with the exposure time of con A. The dysfunctional hepatic macrophages associated with apoptosis were observed earlier than the biochemical and histopathological changes of ALF. In addition, the production of macrophage-related inflammatory cytokines following exposure to con A in vivo or in vitro increased significantly. These observations indicated that the deactivation and apoptosis of hepatic macrophages may be a potential link between inflammation and immunoparesis in ALF.