A split-mouth randomized clinical trial was carried out to assess the effectiveness of sealants in preventing carious ICDAS (International Caries Detection and Assessment System) 3-6 lesions within a 2-year follow-up. We evaluated the effectiveness of 2 types of resin-based sealants, with and without fluoride, their retention rates, and the caries risk factors related to their outcomes. The study included 663 tooth pairs in 400 children (aged 5-15 years) considered to be at high individual caries risk (ICR) and presenting permanent molars free of caries or affected by ICDAS 1-2 lesions. In the first randomization, molars were either randomized to the treatment group receiving a dental sealant or the control group (nontreatment), and in the second randomization the sealant material to be used in the intervention group was selected. Uni- and multivariate Cox proportional hazard models were employed. At the 2-year follow-up, 483 tooth pairs were assessed: sealed molars had 83% (adjusted HR = 0.17; 95% CI: 0.15-0.20) less risk of developing ICDAS 3-6 lesions than molars without sealant. The magnitude of the protective effect was lower among teeth with ICDAS 1-2 lesions or with occlusal deep fissures than without. If the total retention rate of sealants was 70% at 2 years, sealant loss was not associated with the risk of caries (HR = 1.29, 95% CI: 0.92-1.79, p = 0.14). Sealants allow the prevention of new ICDAS 3-6 lesions or progression of noncavitated carious lesions in children at high ICR, and the effect of the sealant was similar regardless of whether it contained fluoride or not.