Endothelin 1 (ET-1) has been shown to have a key role in homeostasis and function of endothelium and maybe fundamental in the relationship between coronary heart disease (CHD) and periodontitis. In this trial, we assessed the influence on serum and salivary ET-1 levels of gingival health, CHD, periodontitis, or a combination of periodontitis-CHD. Clinical and periodontal parameters, were collected from periodontitis patients (n = 34), CHD patients (n = 34), periodontitis + CHD patients (n = 34), and from healthy patients (n = 34) together with saliva and serum samples. The median concentrations of salivary and serum ET-1 were significantly higher in the CHD patients [serum: 1.4(1.1-1.6) pg/ml; saliva 1.2 (0.9-1.6) µmol/g, p < 0.01] and in the periodontitis + CHD patients [serum: 1.7 (1.2-21.8) pg/ml; salivary 1.4(1-1.6) µmol/g, p < 0.001] respect to periodontitis and control patients. Through a univariate regression analysis, c-reactive protein (CRP) and CHD (both p < 0.001) and periodontitis (p = 0.029) were statistically correlated with ET-1 in serum. The multivariate regression analysis demonstrated that only CRP was the statistically predictor of ET-1 in serum(p < 0.001). The multivariate regression analysis in saliva demonstrated that, regarding ET-1 levels the only predictor were CRP (p < 0.001) and total cholesterol (p = 0.042). The present study evidenced that subjects with CHD and periodontitis plus CHD had higher serum and salivary levels of ET-1 compared to subjects with periodontitis and healthy controls. Moreover, only CRP remained a major predictor of increased ET-1 concentrations in both serum and saliva.