Background: Periodontitis has been reported to be associated with coronary artery disease. Research is needed to determine whether therapies that improve periodontal health also reduce systemic marker of inflammation associated with both diseases. Aim: To determine whether sub-antimicrobial dose-doxycycline (SDD) therapy can reduce systemic serum inflammatory biomarker C-reactive protein (CRP) in post-menopausal women who have chronic periodontitis. Settings and Design: The study randomly assigned 128 eligible post-menopausal women with chronic periodontitis to a 90-day, twice-daily regimen of SDD or placebo tablets evaluated for 2 years, as an adjunct to periodontal maintenance therapy. Materials and Methods: The study assayed blood samples for inflammatory mediators at baseline, 1 year, and 2 years. CRP was measured using a high-sensitivity enzyme-linked immunosorbent assay. Results: SDD treatment reduced median high-sensitivity CRP by 18% (primary outcome = 0.02). Conclusion: Ninety-day SDD regimen in post-menopausal women significantly reduced the serum inflammatory biomarker CRP over a 2-year period.