Background: The aim of this study is to evaluate the gene expression of immune-inflammatory markers in gingival biopsies of patients with type 2 diabetes with chronic periodontitis (CP). Methods: Gingival biopsies were harvested from systemically and periodontally healthy patients (SPH), systemically healthy patients with CP (SHCP), and patients with better-controlled and poorly controlled diabetes and CP. The levels of mRNA of interleukin (IL)-17, IL-6, IL-23, IL-10, IL-4, interferon-gamma, toll-like receptor (TLR)-2, TLR-4, osteoprotegerin, receptor activator of nuclear factor-kappa B ligand (RANKL), tumor necrosis factor-a, transforming growth factor-beta, transcription factor forkhead box p3, transcription factor orphan nuclear receptor C2 (RORC2), and receptor of advanced glycation end products (RAGE) were evaluated by quantitative real-time polymerase chain reaction. Results: All CP groups presented higher levels of mRNA of TLR-2, TLR-4, IL-17, RANKL, and RAGE and a higher frequency of IL-17 and TLR-2 mRNA-positive biopsies when compared to SPH (P < 0.05). There was a higher frequency of detection of RORC2 in the biopsies from both groups with diabetes compared to the other groups (P < 0.05). The frequency of IL-4 mRNA-positive tissues was lower in patients with diabetes compared to SHCP (P < 0.05). Conclusion: CP, but not type 2 diabetes mellitus, significantly affected the expressions of the evaluated genes related to the innate and adaptive immune responses. J Periodontol 2012;83:426-434.