Aims: To investigate whether MHC genes are associated with basal pain sensitivity differences in Dark-Agouti (DA) rats and a novel congenic inbred DA.1U rats, whose genetic background is the same as DA rats except for major histocompatibility complex (MHC) genes. Main methods: Mechanical withdrawal threshold (MWT) and heat withdrawal latencies (HWL) were compared in the two rat strains to reflect basal pain sensitivity. Immunohistochemistry was used to observe the expression level of RT1B, representative of MHC class II DQ region, and the basal expression of phosphorylated cAMP response element-binding protein (pCREB) in the L4/L5 spinal cord in the two rat strains. Key findings: The MWT and HWL of DA rats were significantly less than that of DA.1U rats. The expression level of pCREB in the L4/L5 spinal cord in DA rats was greater than that found in DA.1U rats. The expression level of RT1B in the spinal cord was greater in DA rats, which suggested MHC class II DQ region is likely involved in the differences in sensitivity to noxious mechanical and thermal stimulation between the two rat strains. Significance: These results suggest MHC genes are associated with basal pain sensitivity, which may contribute to the identification of pain sensitivity and/or individually tailored pain treatment regimens. © 2010 Elsevier Inc.