This randomized clinical trial compares retention, survival rate, and evolution of caries of newly erupted permanent molars sealed with bioactive self-etching sealants with pre-reacted glass ionomer (S-PRG). A split-mouth clinical trial was conducted with 56 permanent second molars in stages 2 and 3 of crown eruption; ICDAS (International Caries Detection and Assessment System) was between 0 and 2. The molars were randomized and blinded in relation to the side (right or left) that would receive the sealants; the conventional resin sealant (FS), Fluroshield (Dentsply), or bioactive self-etch sealant (BS), BeautiSealant with S-PRG (Shofu). The sealants were compared in terms of retention, quality of sealant remnant (anatomical shape, marginal adaptation, surface texture, and marginal discoloration), and development of caries by ICDAS after 1, 6, and 12 months. The Wilcoxon, x² of independence, Kaplan-Meier, and Mantel-Cox survival statistical tests were applied (α = 5%). The total retention was higher for FS (57.1%) at all periods, and there was no difference in the quality of sealants at all periods. The ICDAS decreased after 6 (p = 0.025) and 12 months (p = 0.027) for both materials. Despite the lower retention of BS, the clinical quality of sealants over 12 months were similar. Teeth sealed with BS presented higher sound teeth predominance (ICDAS 0) compared to FS sealant, even with a higher loss of material. Eruption of permanent molars is a relevant period, and the prevention/management of initial caries is essential in these critical stages. Sealants can be an important prevention strategy. After 12 months of follow-up, there was a major failure of the bioactive sealant but without the development of caries lesions. Copyright © 2021 Elsevier Ltd. All rights reserved.