Theiler's murine encephalomyelitis virus (TMEV) induces a demyelinating disease in susceptible strains, which clinically and histopathologically resembles human multiple sclerosis. Since bacterial LPS produced by Gram-negative bacteria is known to potentiate an immune response and trigger resident central nervous system cells to produce various inflammatory cytokines, we examined the ability of LPS to affect resistance to TMEV-induced demyelinating disease (TMEV-IDD). Intraperitoneal injection of LPS, concomitant with intracerebral of genetically resistant C57BL/6 mice with TMEV, resulted in clinical symptoms in approximately 50% of the group. The increase in susceptibility following LPS treatment correlated with the enhanced levels of TMEV-specific delayed-type hypersensitivity and T cell proliferative responses. Similar treatment with LPS, however, did not accelerate the clinical course of susceptible (SJL/J) or intermediately susceptible (C3H) mice. The LPS-treated C57BL/6 mice displayed an increased viral persistence in the central nervous system when compared with nontreated control mice. Intraperitoneal administration of IL-1 beta could mimic the LPS effect in C57BL/6 mice, suggesting that the increase in susceptibility to TMEV-IDD may function via IL-1 produced following LPS stimulation.