To investigate the expression of protein tyrosine phosphatase non-receptor type 2 (PTPN2) and nuclear factor-kappaB (NF-kappaB), as well as the relationship between their expression and periodontal destruction in mice with diabetic periodontitis.Four weeks old healthy C57BL/6J mice were randomly divided into normal control group (Group N), periodontitis group (Group P) and diabetic periodontitis group (Group DP), and each group had six mice. Mice in Group P were inoculated Porphyromonas gingivalis orally to induce periodontitis. Mice in Group DP had high sugary and fatty food, streptozotocin intraperitoneal injection and Porphyromonas gingivalis oral inoculation to induce diabetic periodontitis. All mice were sacrificed 4 weeks after the last bacterium inoculation of Groups P and DP. Stereo microscope was chosen to detect morphological changes and bone loss areas of the alveolar bone. Hematoxylin-eosin (HE) staining was selected to observe loss heights of periodontal attachment. Immunohistochemical staining was used to detect PTPN2 and NF-kappaB expression in periodontal tissues.Group P and Group DP had significantly more attachment loss heights and areas than Group N (P < 0.05), and showed less PTPN2 expression (P < 0.05) and higher NF-kappaB levels (P < 0.01).PTPN2 may negatively regulate the development of diabetic periodontitis, while NF-kappaB may have opposite effects. PTPN2 down-regulation might contribute to NF-kappaB over-expression leading to exacerbated periodontal destruction.