OBJECTIVES: The aim of the present study is to estimate the annual direct and indirect costs in patients with a history of or at risk for atherothrombosis in Greece, using a bottom-up approach. METHODS: A multicentre, prospective, cost-of-illness study was conducted between January 2007 and December 2009. In this study, 800 patients with coronary artery disease (CAD) or cerebrovascular disease (CD) or peripheral artery disease (PAD) or multiple cardiovascular risk factors (MRF) were recruited from 11 major hospitals in Greece. All patients were followed up for 12 months. Resources used for the care of patients within the healthcare system and productivity losses during the follow-up period were recorded. The annual direct and indirect costs were calculated by combining these data with unit costs. RESULTS: The mean annual total cost was €5,940/patient (€5,416–€6,522). This cost ranges from €9,963/patient (€8,515–€11,868) for PAD group to €1,761/patient (€1,462– €2,232) for MRF group. The mean annual direct healthcare cost was €5,056 /patient (€4,653–€5,507). This cost escalates from €1,623 /patient (€1,319– €2,073) for MRF group to € 8,697 /patient (€7,648– €9,695) for PAD group. The annual direct healthcare costs was mainly driven by vascular intervention costs among CAD and PAD patients, (50.6% and 46.5%, respectively)  and by the simple hospitalization cost among CD and MRF patients (67.7% and 35.7%, respectively). The mean annual indirect cost was €979 (€386– €1,395), €441 (€142- €835), €525 (€148 – €1,137) and €29 (€1- €87) per patient in the CD, CAD, PAD and MRF groups, respectively. The total annual expenditures related to atherothrombosis, in Greece, are estimated to be 7.5 billion € at a national level.  CONCLUSIONS: The findings of the THESIS study indicate, for the first time, the high economic burden of atherothrombosis in Greece, since the direct healthcare cost related to atherothrombosis management accounts for almost 25% of annual healthcare expenditures.