The study identifies mutations in the *Toll-like receptor 4* (*Tlr4*) gene as the cause of endotoxin tolerance in two inbred mouse strains, C3H/HeJ and C57BL/10ScCr. Genetic mapping localized the *Lps* locus to a 0.9-cM interval on chromosome 4, spanning 1.7 Mb. Within this region, three transcription units were identified, including *Tlr4*. C3H/HeJ mice harbor a point mutation in *Tlr4* that substitutes a highly conserved proline with histidine at codon 712, while C57BL/10ScCr mice exhibit a deletion of *Tlr4*. These mutations strongly support the hypothesis that altered *Tlr4* function is responsible for endotoxin tolerance in these strains. The findings highlight the critical role of *Tlr4* in innate immune responses to bacterial lipopolysaccharide (LPS) and provide insights into the genetic basis of LPS-induced inflammation.The study identifies mutations in the *Toll-like receptor 4* (*Tlr4*) gene as the cause of endotoxin tolerance in two inbred mouse strains, C3H/HeJ and C57BL/10ScCr. Genetic mapping localized the *Lps* locus to a 0.9-cM interval on chromosome 4, spanning 1.7 Mb. Within this region, three transcription units were identified, including *Tlr4*. C3H/HeJ mice harbor a point mutation in *Tlr4* that substitutes a highly conserved proline with histidine at codon 712, while C57BL/10ScCr mice exhibit a deletion of *Tlr4*. These mutations strongly support the hypothesis that altered *Tlr4* function is responsible for endotoxin tolerance in these strains. The findings highlight the critical role of *Tlr4* in innate immune responses to bacterial lipopolysaccharide (LPS) and provide insights into the genetic basis of LPS-induced inflammation.