Background: This triple-blind, randomized controlled trial evaluated and compared the effectiveness of resin-based sealants (RS) and giomer-based sealants (GS) in preventing dental caries in erupting permanent molars in children. Methods: Erupting permanent molars in children (aged 5–14 years) with non-cavitated carious lesions (International Caries Detection and Assessment System scores 1–2) were enrolled and randomly assigned to receive either GS or RS. Clinical assessments were performed at 3, 6, and 12 months. The primary outcome was sealant retention. The secondary outcomes included the incidence of caries and sealant quality (anatomical form, marginal adaptation, superficial texture, and marginal discoloration). Results: Among a total of 88 erupting permanent molars in 88 children (aged 6.93–12.11 years) included in the analysis, the RS group demonstrated significantly higher total retention compared with the GS group at both 6 (90.7% (39/43) vs. 59.1% (26/44); p = 0.002) and 12 (61.9% (26/42) vs. 17.1% (7/41); p < 0.001) months. Regarding caries, no new lesions were detected in the RS group throughout the study period. In the GS group, new caries were identified in 2.3% (1/44) of teeth at 6 months and 4.9% (2/41) at 12 months. As only two caries events were observed overall, this study was underpowered to detect between-group differences in caries incidence. However, a weak, significant positive correlation was observed between sealant loss and caries development at 12 months (r = 0.221, p = 0.045). Conclusions: While both the RS and GS were associated with a low incidence of caries over 12 months, the RS demonstrated significantly superior retention and overall clinical quality. These findings highlight the clinical trade-off between the enhanced durability of RS and the potential for a simplified application with GS. Further long-term studies are warranted to fully evaluate these differences. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT05969756.
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