OBJECTIVES: To evaluate the cost-effectiveness of an imaging diagnostic strategy for stable coronary artery disease (CAD) guided by a new model to estimate the pre-test likelihood of disease that integrates specific circulating biomarkers with common clinical variables using data collected through the EVINCI study. METHODS:  In the clinical standard path (CSP) pre-test likelihood of disease was estimated by the Genders model (based on age, sex and symptoms) while the new clinical-biohumoral path (CBP) included the integration of previously selected bio-humoral predictors of CAD (HDL-cholesterol, aspartate-transaminase and C-reactive protein) to define the pre-test likelihood. In both paths, according to the 2013 ESC-Guidelines for management of stable CAD, the pre-test likelihood guided further examinations: no other test for low probability (<15%), non-invasive imaging in intermediate probability (15%-85%) and direct invasive coronary angiography (ICA) for high probability (>85%). Effectiveness was defined in terms of correct diagnosis at ICA. Costs of the diagnostic pathways were calculated per-patients considering reimbursement of non-invasive and invasive examinations as well as biomarkers assay in the CBP. All costs were expressed in Euro 2013. RESULTS: : Considering 487 subjects enrolled in the EVINCI study because of suspected CAD and having a complete clinical, bio-humoral and imaging profile, the CBP dominates the CSP being more effective and less costly. Specifically, CBP allowed for 90.6% (±29.3%) correct diagnoses with a mean cost of 352.9 Euros (±752.5), while CSP correctly diagnosed 88.9% (±29.3%) of cases at a mean cost of 615.6 Euros (±861.1). Results did not change when accounting for missed CAD diagnoses. CONCLUSIONS: The estimation of pre-test likelihood of CAD integrating circulating biomarkers and clinical variables allows for more accurate and more cost-effective diagnostic strategies, avoiding unnecessary diagnostic tests. The new predictive model is an effective gate-keeper to non-invasive and invasive imaging tests in patients with symptoms of stable CAD.