Abstract Background Periodontal disease (PD) is an infectious clinical entity characterized by the destruction of supporting tissues of the teeth as the result of a chronic inflammatory response in a susceptible host. It has been proposed that PD as subclinical infection may contribute to the etiology and to the pathogenesis of several systemic diseases including Atherosclerosis. A number of epidemiological studies link periodontal disease/edentulism as independent risk factor for acute myocardial infarction, peripheral vascular disease, and cerebrovascular disease. Moreover, new randomized controlled clinical trials have shown an improvement on cardiovascular surrogate markers (endothelial function, sICAM, hsPCR level, fibrinogen) after periodontal treatment. Nonetheless, such trials are still limited in terms of external validity, periodontal treatment strategies, CONSORT-based design and results consistency/extrapolation. The current study is designed to evaluate if periodontal treatment with scaling and root planning plus local delivered chlorhexidine improves endothelial function and other biomarkers of cardiovascular disease in subjects with moderate to severe periodontitis. Methods/Design This randomized, single-blind clinical trial will be performed at two health centers and will include two periodontal treatment strategies. After medical/periodontal screening, a baseline endothelium-dependent brachial artery flow-mediated dilatation (FMD) and other systemic surrogate markers will be obtained from all recruited subjects. Patients then will be randomized to receive either supragingival/subgingival plaque cleaning and calculus removal plus chlorhexidine (treatment group) or supragingival plaque removal only (control group). A second and third FMD will be obtained after 24 hours and 12 weeks in both treatment arms. Each group will consist of 49 patients (n = 98) and all patients will be followed-up for secondary outcomes and will be monitored through a coordinating center. The primary outcomes are FMD differences baseline, 24 hours and 3 months after treatment. The secondary outcomes are differences in C-reactive protein (hs-CRP), glucose serum levels, blood lipid profile, and HOMA index. Discussion This RCT is expected to provide more evidence on the effects of different periodontal treatment modalities on FMD values, as well as to correlate such findings with different surrogate markers of systemic inflammation with cardiovascular effects. Trial registration number ClinicalTrials.gov Identifier: NCT00681564.