Effective preventive strategies for cardiometabolic disease (CMD) are needed. We aim to establish the effectiveness of a stepwise CMD risk assessment followed by individualized treatment if indicated compared to care as usual. We conducted a RCT between 2014 and 2017. Individuals (45–70 years) without CMD or CMD risk factors were invited for stepwise CMD risk assessment through a risk score (step1), additional risk assessment at the practice in case of high-risk (step2) and individualized follow-up treatment if indicated (step3). We compared newly detected CMD and newly prescribed drugs during one-year follow-up, and change in CMD risk profile between baseline and one-year follow-up among participants who completed step2 to matched controls. A CMD was diagnosed almost three times more often (OR 2.90, 95% CI 2.25: 3.72) in the intervention compared to the control group, in parallel with newly prescribed antihypertensive and lipid lowering drugs (OR 2.85, 95% CI 1.96: 4.15 and 3.23, 95% CI 2.03: 5.14 respectively). Waist circumference significantly decreased between the intervention compared to the control group (mean −3.08 cm, 95% CI −3.73: −2.43). No differences were observed for changes in BMI and smoking. Systolic blood pressure (mean −2.26 mmHg, 95% CI −4.01: −0.51) and cholesterol ratio (mean −0.11, 95% CI −0.19: −0.02) significantly decreased within intervention participants between baseline and one-year follow-up. In conclusion, implementation of the CMD prevention program resulted in the detection of two- to threefold more patients with CMD. A significant drop in systolic blood pressure and cholesterol levels was found after one year of treatment. Modelling of these results should confirm the effect on long term endpoints. Trial registration: Dutch trial Register number NTR4277.