SummaryMycobacterium lepraemurium (MLM) infection increases the sensitivity of mice to lipopolysaccharide (LPS) as do infections with other intracellular parasites. Tumour necrosis factor (TNF), lymphocyte activating factor (LAF) and increased levels of various lysosomal and cytoplasmic enzymes were found in serum samples taken 2 h after intravenous injection of a small dose of LPS suggesting that damage to a variety of cell types, including macrophages, had occurred. Sera from moribund MLM‐infected mice not injected with LPS also demonstrated significant levels of TNF compared with controls. Intravenous injections of silica into leprous mice also led to increased levels of serum lysosomal and cytoplasmic enzymes but did not give rise to a significant amount of TNF or LAF. Moreover, in contrast to LPS treatment, the injection of silica did not lead to the death of leprous mice. These findings suggest that the phagocytic cells of the infected animals did not contribute to the production of these mediators after LPS challenge. Rather, the non‐phagocytic granuloma macrophages or other unidentified cell types seemed to provide the main source of the monokines TNF and LAF in vivo in the present model. These mediators may have important implications for the immunopathology of MLM infect