Background: The present study evaluates effects of non-surgical periodontal treatment on serum biomarkers in patients with type 2 diabetes mellitus (T2DM) and chronic periodontitis who participated in the Diabetes and Periodontal Therapy Trial (DPTT); and associations among diabetes markers, serum biomarkers, and periodontal measures in these patients. Methods: DPTT participants randomized to receive immediate or delayed non-surgical periodontal therapy were evaluated at baseline and 6 months. Serum samples from 475 participants with 6-month data were analyzed for the following biomarkers: 1) high sensitivity C-reactive protein; 2) E-selectin; 3) tumor necrosis factor (TNF)-α 4) vascular cell adhesion molecule (VCAM); 5) interleukin (IL)-6; 6) IL-8; 7) intercellular adhesion molecule; and 8) IL-10. Changes in biomarker levels from baseline and correlations among biomarker levels and clinical findings were analyzed. Results: No differences between treatment and control groups were observed for any biomarkers at baseline or 6 months (P >0.05 for all variables). VCAM levels increased by an average (standard deviation) of 17.9 (99.5); ng/mL (P = 0.006) and E-selectin decreased by 2.33 (16.08) ng/mL (P = 0.03) in the treatment group after 6 months. E-selectin levels were significantly correlated with DM-related variables (hemoglobin A1c [HbA1c] and fasting glucose) at baseline and with 6-month change in both groups; no significant correlations were found among periodontal clinical parameters and serum biomarkers or DM-related variables. Neither HbA1c or body mass index varied during the study period in either study group. Conclusions: Non-surgical periodontal therapy and periodontal disease severity were not associated with significant changes in serum biomarkers in DPTT participants during the 6-month follow-up. Correlations among changes in E-selectin, IL-6, and DM-related variables suggest that T2DM may be the primary driver of systemic inflammation in these patients.