BACKGROUND The preschool years offer a unique window of opportunity to instill healthy life-style behaviors and promote cardiovascular health. OBJECTIVES This study sought to evaluate the effect of a 3-year multidimensional school-based intervention to improve life-style-related behaviors. METHODS We performed a cluster-randomized controlled intervention trial involving 24 public schools in Madrid, Spain, that were assigned to either the SI! Program intervention or the usual curriculum and followed for 3 years. The SI! Program aimed to instill and develop healthy behaviors in relation to diet, physical activity, and understanding how the human body and heart work. The primary outcome was change in the overall knowledge, attitudes, and habits (KAH) score (range 0 to 80). The intervention's effect on adiposity markers was also evaluated. RESULTS A total of 2,062 children from 3 to 5 years of age were randomized. After 3 years of follow-up, the overall KAH score was 4.9% higher in children in the intervention group compared with the control group (21.7 vs. 16.4; p 0.001). A peak effect was observed at the second year (improvement 7.1% higher than in the control group; p 0.001). Physical activity was the main driver of the change in KAH at all evaluation times. Children in the intervention group for 2 years and 1 year showed greater improvement than control subjects (5.9%; p 0.001 and 2.9%; p = 0.002, respectively). After 3 years, the intervention group showed a higher probability than the control group of reducing the triceps skinfold z-score by at least 0.1 (hazard ratio: 1.40, 95% confidence interval: 1.04 to 1.89; p = 0.027). CONCLUSIONS The SI! Program is an effective strategy for instilling healthy habits among preschoolers, translating into a beneficial effect on adiposity, with maximal effect when started at the earliest age and maintained over 3 years. Wider adoption may have a meaningful effect on cardiovascular health promotion. (author abstract)