Background: The systemic inflammation in both metabolic syndrome (MetS) and periodontitis is a common denominator of the association of these conditions with higher risk of atherosclerosis. The current study investigates whether periodontal therapy may reduce systemic inflammation in patients with MetS and reduce cardiovascular risk. Methods: A parallel-arm, double-blind, randomized clinical trial of 1-year duration in patients with MetS and periodontitis was conducted. Participants were randomized to an experimental treatment group (ETG) (n = 82) that received plaque control and root planing plus amoxicillin andmetronidazole or to a control treatment group (CTG) (n = 83) that received plaque control instructions, supragingival scaling, and two placebos.Risk factors for cardiovascular disease were recorded; serum lipoprotein cholesterol, glucose, body mass index (BMI), C-reactive protein (CRP) and fibrinogen concentrations, and clinical periodontal parameters were assessed at baseline and every 3 months until 12 months after therapy. The primary and secondary outcomes were changes in CRP and fibrinogen levels, respectively. Results: The baselinepatients' characteristics of both groupswere similar. No significant changes in lifestyle factors, frequency of hypertension, BMI, serum lipoprotein cholesterol, and glucose levels were observed during the study period. The periodontal parameters significantly improved in both groups 3 months after therapy (P = 0.0001) and remained lower than baseline up to 12 months. The improvement of periodontal status was significantly greater in the ETG (P = 0.0001). A multiple linear regression analysis, controlled for sex, smoking, hypertension, and extent of periodontitis, demonstrated that CRP levels decreased with time and that this reduction was significant at 9 (P = 0.024) and 12 (P = 0.001) months in both groups, without difference between the groups. Fibrinogen levels significantly decreased in the ETG at 6 and 12 months but not in the CTG. Conclusion: Reduction of periodontal inflammation eitherwith root planing and systemic antibiotics or with plaque control and subgingival scaling significantly reduces CRP levels after 9months in patients with MetS.