Objective: To compare circulating and gingival crevicular fluid (GCF) substance P concentrations in well- and poorly controlled type 2 diabetic patients with chronic periodontitis. Method and Materials: Forty-five serum and 90 GCF samples were collected from diabetic patients with periodontal disease, and the concentrations of substance P were quantified by radioimmunoassay. Results: Serum substance P levels were higher in the poorly controlled diabetic group than in patients with good glycemic control (P = .01); within the poorly controlled group, patients with severe attachment levels had the highest circulating substance P levels (P = .02). Additionally, the diseased sites showed higher substance P levels than control sites (P = .0016). The GCF substance P concentrations in diseased sites correlated significantly with clinical findings such as Plaque Index (r = 0.51, P = .001) and bleeding on probing (r = 0.35, P = .029). Conclusion: Within the limits of this study, our preliminary findings indicate that periodontal inflammation may influence circulating and GCF substance P levels in poorly controlled diabetic subjects. Keywords: diabetes, gingival crevicular fluid, neurogenic inflammation, neuropeptides, substance P