© 2016, Springer-Verlag Berlin Heidelberg.Objectives: To evaluate and compare the clinical retention of a resin-based fissure sealant placed with an intermediate layer of etch-and-rinse (ER) or self-etch (SE) adhesives. Materials and methods: Two hundred twenty-eight sealants were placed in 57 children with previously unsealed, caries-free permanent first molars, employing a split-mouth design. The teeth were randomized into four groups (n = 57 teeth/groups) according to the adhesive system placed under the tested sealant (Delton FS+; Dentsply). Group 1 (control): no bonding agent (conventional acid-etch sealant); group 2: prior enamel etch + ER adhesive (XP Bond; Dentsply); group 3: SE adhesive (Clearfil SE Bond; Kuraray) without prior etching; and group 4: prior enamel etch + SE adhesive (Clearfil SE Bond). Clinical assessments were performed according to modified USPHS criteria at 1, 3, 6, 12, 18, and 24 months. The data were analyzed statistically using Fisher’s Exact test, the Kaplan-Meier analysis, and the Log-rank test. Results: At 24 months, sealants bonded with XP Bond and Clearfil SE Bond with prior enamel etching showed similar retention rates (p > 0.05), and these rates were significantly better than the rates of the conventional sealant and Clearfil-SE groups (p < 0.05). There was no significant difference between the retention rates of the latter two groups (p > 0.05). The cumulative survival rates on palatal/buccal surfaces showed similar outcomes as with occlusal surfaces: XP Bond (94%), Clearfil SE Bond + acid-etch (94%), conventional sealant (52%), and Clearfil SE Bond only (37%). Conclusions: Application of the tested ER adhesive and the SE adhesive with enamel etching significantly improved the clinical retention of Delton-FS over the 24-month period. Clinical relevance: The use of a resin-based fissure sealant placed with ER or SE adhesive with prior acid-etching yielded better retention than the conventional sealant over the 24-month period.