OBJECTIVES To evaluate the cost-effectiveness (CE) of imaging-guided strategies for the diagnosis of significant coronary artery disease (CAD) in patients with intermediate pre-test likelihood. METHODS Significant CAD was defined at invasive coronary angiography (ICA) as >50% stenosis in the left main or >70% stenosis in a major coronary vessel or 30-70% stenosis with fractional flow reserve ≤0.8.Nine diagnostic strategies were compared using a CE analysis. Strategies included the use of one single or two combined non-invasive imaging tests (CTCA as first line test and then stress ECHO, CMR, PET or SPECT) followed by ICA in the case of positivity of the single test or both non-invasive examinations in the case of combinations. ICERs were obtained using per-patient data collected throughout the EVINCI multicentre European study. Strategy costs were calculated using examination country-specific reimbursements, while effectiveness was defined as the percentage of correct diagnosis. All costs were converted to Euro 2012 and adjusted using PPP. A propensity-score adjustment was used in the analysis and 95%CI were obtained with non-parametric bootstrap. RESULTS Among the strategies analysed only three resulted cost-effective for the diagnosis of significant CAD. These included stress ECHO and CTCA as single non-invasive test, CTCA first then ECHO, CTCA first and then stress PET, all followed by ICA when required. Stress ECHO approach was the least costly but also the least effective, while CTCA alone [ICER: 2345 (2287-2400)] or in combination with PET [ICER: 5227(5161-5296)] had increasingly higher effectiveness for a willingness to pay (WTP) exceeding 2,000 Euro and 5,000 Euro, respectively. CONCLUSIONS Results from the health-economic analysis of the EVINCI study showed that stress ECHO guided diagnostic strategy could be cost-effective when the WTP is low. Strategies involving CTCA alone or as first line exam followed by stress PET could allow a more accurate diagnostic workflow for higher WTP.