To investigate the relationship between sensitivity to toluene exposure and genetic background, male congenic mice, C57BL/10 (H-2(b)) and B10.BR/Sg (H-2(k)) were exposed to 0, 5, and 50 ppm toluene for 6 h per day, 5 days per week for 6 weeks. Groups of mice were injected with ovalbumin (OVA) intraperitoneally before starting exposure schedule and these mice were then challenged with aerosolized OVA as a booster. Following 24 h of the last exposure, the spleens were collected. We examined spleen cell proliferation using DNA synthesis and T-helper 1/2-related transcription factor genes in spleen of two congenic mice using real-time reverse transcriptase-polymerase chain reaction. Although lipopolysaccharide-induced (LPS-induced) cell proliferation was significantly increased in 50 ppm toluene-exposed, nonimmunized B10.BR mice but not in C57BL/10 mice, exposure to 50 ppm toluene significantly decreased LPS-induced cell proliferation in immunized B10.BR mice. The expression of transcription factor forkhead box P3, signal transducers and activators of transcription (STAT) 5 and STAT6 mRNAs was significantly increased in spleen from 5 ppm toluene-exposed, OVA-immunized B10.BR mice, but not in those of C57BL/10 mice. Although there may be other differences unrelated to H-2 locus between the congenic mice of the same background, the findings of the present study strongly suggest a possible role of H-2 locus in the toluene-induced immune disturbance.