Abstract Background Cardiometabolic diseases (CMD) are the major cause of death worldwide and are associated with a lower quality of life and high healthcare costs. To prevent a further rise in CMD and related healthcare costs, early detection and adequate management of individuals at risk could be an effective preventive strategy. The objective of this study was to determine long-term cost-effectiveness of stepwise CMD risk assessment followed by individualized treatment if indicated compared to care as usual. A computer-based simulation model was used to project long-term health benefits and cost-effectiveness, assuming the prevention program was implemented in Dutch primary care. Methods A randomized controlled trial in a primary care setting in which 1934 participants aged 45–70 years without recorded CMD or CMD risk factors participated. The intervention group was invited for stepwise CMD risk assessment through a risk score (step 1), additional risk assessment at the practice in case of increased risk (step 2) and individualized follow-up treatment if indicated (step 3). The control group was not invited for risk assessment, but completed a health questionnaire. Results of the effectiveness analysis on systolic blood pressure (− 2.26 mmHg; 95% CI − 4.01: − 0.51) and total cholesterol (− 0.15 mmol/l; 95% CI − 0.23: − 0.07) were used in this analysis. Outcome measures were the costs and benefits after 1-year follow-up and long-term (60 years) cost-effectiveness of stepwise CMD risk assessment compared to no assessment. A computer-based simulation model was used that included data on disability weights associated with age and disease outcomes related to CMD. Analyses were performed taking a healthcare perspective. Results After 1 year, the average costs in the intervention group were 260 Euro higher than in the control group and differences were mainly driven by healthcare costs. No meaningful change was found in EQ 5D-based quality of life between the intervention and control groups after 1-year follow-up (− 0.0154; 95% CI − 0.029: 0.004). After 60 years, cumulative costs of the intervention were 41.4 million Euro and 135 quality-adjusted life years (QALY) were gained. Despite improvements in blood pressure and cholesterol, the intervention was not cost-effective (ICER of 306,000 Euro/QALY after 60 years). Scenario analyses did not allow for a change in conclusions with regard to cost-effectiveness of the intervention. Conclusions Implementation of this primary care-based CMD prevention program is not cost-effective in the long term. Implementation of this program in primary care cannot be recommended. Trial registration Dutch Trial Register NTR4277, registered on 26 November 2013