Murine resistance to development of toxoplasmic encephalitis (TE) has recently been mapped to the D region of the major histocompatibility complex (H-2). Since the gene for tumor necrosis factor alpha (TNF-alpha) is located 5' of the D region and TNF-alpha has been implicated as playing a role in neurological diseases, we were interested in determining the relationship of TNF-alpha production to TE resistance. We have demonstrated that resistance to TE in inbred mice can be correlated with specific restriction fragment length polymorphisms and microsatellite variants in the TNF-alpha gene. Mice that are susceptible to TE express elevated levels of TNF-alpha mRNA in brain tissue 6 wk after infection with the ME49 strain of Toxoplasma gondii. Resistant mice and all mice that are uninfected show no detectable TNF-alpha mRNA expression in brain tissue. Differences in the TNF-alpha gene between susceptible and resistant mice have been localized to the first intron, the promoter, and the 3' end of the TNF-alpha gene. These data implicate differences in regulation of TNF-alpha production in brain tissue as contributing to differences in susceptibility to development of TE.