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.