To determine the impact of periodontal treatment on systemic markers of inflammation in patients with metabolic syndrome (MetS) and periodontitis. In this parallel-arm, double-blind, randomized controlled clinical trial, 63 patients with MetS and severe periodontitis were randomly assigned to receive either intensive periodontal treatment (IPT; scaling and root planing plus azithromycin 500 mg every day for 3 days) or minimal periodontal treatment (MPT; supragingival professional mechanical plaque removal plus a placebo). The primary outcome was the impact of the tested interventions on high-sensitivity C-reactive protein (hs-CRP) serum levels at 6 months. As secondary outcomes, differences in the levels of cytokines, markers of prothrombotic states, carbohydrate and lipid metabolism, as well as blood pressure, were measured at 3 and 6 months after therapy. The intention-to-treat population consisted of 63 subjects randomly assigned to either the MPT (n = 31) or the IPT (n = 32) group. At baseline, mean hs-CRP was 3.9 mg/L (standard deviation [SD] = 2.9) and 3.9 mg/L (SD = 3.4), respectively, and no significant differences in cardiometabolic risk profiles were detected between the groups. Adjusting for baseline hs-CRP, sex, age, smoking status and body mass index, hs-CRP at 6 months was 1.2 mg/L (95% CI 0.4; 2.0; P = .004) lower in the IPT group than in the MPT group. In the secondary outcomes, significant reductions in IL-1β, TNF-α, HbA1c and blood pressure were observed in the IPT group at 3 months compared with the MPT group. Effective periodontal treatment significantly reduced hs-CRP after 6 months in patients with MetS and severe periodontitis. Periodontal therapy might be useful to reduce cardiovascular risk in these patients.