Low-dose aspirin is a standard care for secondary prevention of cardiovascular disease (CVD). Its use in primary prevention is less widely accepted, however, despite recent meta-analyses and US and European guidelines supporting its use in individuals at increased CVD risk. The aim of this study was to define which patients should receive aspirin for primary prevention of CVD using data from four European countries. Based on the clinical data from two meta-analyses, a state-transition model was developed to compare the costs and effects of no treatment and low-dose aspirin as primary prevention for CVD over 10 years. The model was applied to patients at different 10-year risks (2-5%) of fatal CVD according to the SCORE equation. Direct costs from the perspective of the healthcare payer were used (base year 2003). Country-specific discounting was applied. Treating patients with a 10-year risk of fatal CVD of 2% or higher with low-dose aspirin resulted in lower total costs and more quality-adjusted life-years gained in the UK, Germany and Spain. In Italy, savings started at a 10-year fatal CVD risk of 3%. This difference was due to the higher cost of gastrointestinal bleeding in Italy. Monte Carlo analysis showed that aspirin was dominant in more than 90% of patients at a 10-year risk of 4% and 5% in the four countries. In conclusion, low-dose aspirin treatment becomes cost-saving at a very low 10-year risk of fatal CVD. The cost of gastrointestinal bleeding defines the level at which low-dose aspirin becomes cost-saving.