IL-4- and IL-6-producing cells in human periodontal disease tissues were investigated using immunohistochemical and in situ hybridization techniques. Immunohistochemical analysis demonstrated the presence of IL-4-producing cells within the CD45RO+ subset and the percentage of IL-4+ cells was significantly higher in periodontal lesions than in gingivitis tissues (p < 0.01). The percentage of IL-6-producing memory cells was higher in periodontal lesions compared with gingivitis tissues, although it was not statistically significant (p > 0.05). A reverse tendency in IL-4- and IL-6-positive cells was observed in a few individual cases. No IL-4 mRNA could be detected using the in situ hybridization technique. However, high levels of IL-6 mRNA were present in clinically healthy tissues, with a further increase in both epithelium and connective tissues affected by gingivitis, although only the former was significant (p < 0.025). There was a significant decrease in IL-6 mRNA in both the connective tissue (p < 0.025) and epithelium (p < 0.01) in periodontitis tissues compared with levels in gingivitis tissues. However, the levels of IL-6 mRNA in periodontal tissues were high compared with those of IL-1 mRNA, which was used in this study as a positive control. These results suggest that Th2-type cells may accumulate in periodontal lesions.