Purpose: To determine the effectiveness of fluoride varnish (FV) in preventing caries lesions on the erupting first permanent molars (FPM) of high-risk children. Materials and Methods: A randomised parallel-blinded clinical trial was conducted with a sample of 180 children between 6 and 7 years of age with at least one sound erupting FPM attending a public school in the Dominican Republic. Children were randomly assigned to three groups, one control and two experimental groups, which received FV application every 3 or 6 months. All the children received fluoride toothpaste (1450 ppm), toothbrush, diet counseling, and oral health recommendations every three months. The development of caries lesions was assessed at twelve months using ICDAS. Results: A total of 157 children completed the study, of which 51.0% were female. At the end of the study, 53 participants comprised the control group, 54 were included in the every-3-months (3-month) FV group, and 50 belonged to the every-6-months (6-month) FV group. Adjusted ORs were calculated to compare lesion development between the groups. The results showed that the control group was more likely to develop caries lesions in comparison to the 3-month FV group, with an associated AOR of 1.46 (95% CI: 1.18 to 1.81, p = 0.001). Likewise, applying FV every six months as opposed to every three increased the odds of developing caries with a significant AOR of 1.29 (95% CI: 1.03 to 1.64, p = 0.029). Conclusion: FV application every three months can be recommended to prevent caries lesions on the erupting first permanent molars of high-risk populations. Keywords: dental caries, fluoride varnishes, prevention