Background: To compare the contribution of ‘population’ and ‘high-risk’ approaches to prevention, with regard to their impact on population health in the Netherlands between 1970 and 2010. Methods: Preventive interventions that have had an impact on mortality and morbidity rates were identified using published evaluation studies and routinely collected mortality and morbidity data. These interventions were then classified into population versus high-risk approaches, depending on whether they were targeted to groups identified on the basis of their risk of disease. Results: In the period 1970–2010, 22 new preventive interventions were introduced, which altogether avoided about 16 000 deaths and several hundred thousand disease cases per year in the Netherlands. Tobacco control and road safety measures had the largest impact. Preventive interventions based on a high-risk approach, such as hypertension detection and control and cancer screening, accounted for approximately one quarter of the total health gain. Conclusions: In the period 1970–2010, considerably larger health gains have been achieved with the population approach than with the high-risk approach to prevention. National prevention policies should make judicious use of these complementary approaches to maximize health gain.