DA strain of Theiler's murine encephalomyelitis virus (TMEV) produces a biphasic disease with an initial self-limited acute gray matter polioencephalomyelitis in all strains of mice followed by, in the case of certain susceptible strains of mice, a chronic inflammatory demyelination of the spinal cord with a persistent virus infection. A pathogenic role for T-helper 1 (Th1) cells during the demyelinating phase of disease has been proposed. We characterized the cytokine mRNA expression in the brain and spinal cord of susceptible and resistant strains of mice during the early encephalomyelitic disease and the late demyelination, using a semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) assay. At the time of the encephalomyelitis, both resistant and susceptible mice expressed proinflammatory cytokine mRNAs followed by T-cell derived mRNAs; susceptible mice expressed more IL-12 p40 mRNA than resistant mice. During this early disease, there was no significant difference in Th1 cytokine mRNA expression in the brain and spinal cord among the four strains and relatively little Th2 type cytokine upregulation above levels seen in mock-infected controls. During the late demyelinating disease, susceptible but not resistant mice had evidence of viral genome and a continuous expression of Th1 type cytokine mRNAs. The expression of Th2 cytokine mRNAs varied among the different strains and did not correlate with susceptibility or resistance. The results indicate the complexity of cytokine mRNA expression following TMEV infection and the dependence of the expression on disease pathology, the time following infection and the genetics of the host.