Purpose: To evaluate the influence of application protocol on the shear bond strength (SBS) and nanoleakage of simplified adhesives over 18 months. Materials and Methods: 810 dentin slices were obtained from 405 caries-free human molars. They were randomly assigned to 54 experimental groups resulting from the combination of "adhesive" (Adper Scotchbond 1XT [S1XT], Solobond M [SM], Scotchbond Universal Adhesive in etch-and-rinse mode [SUER] and self-etch mode [SUSE], Adper Easy Bond [EB], Clearfil S3 Bond Plus [CS3]), "application protocol" (manufacturer's instructions [MI], two extra layers of adhesive [EL], hydrophobic resin layer [HL]), and "aging time" (24 h [24H], 6 months [6M], and 18 months [18M] in water). SBS tests were carried out using a Watanabe device followed by failure mode analysis. For the nanoleakage study, specimens from 54 additional molars were prepared as previously described, immersed in ammoniacal silver nitrate, and evaluated with SEM. SBS data were analyzed with ANOVA followed by Tukey's post-hoc tests; failure mode data were analyzed using chi-squared tests (α = 0.05). Nanoleakage data were analyzed with the Kruskal-Wallis test followed by LSD tests (α = 0.05). Results: After 18M, S1XT and SUSE achieved the highest mean SBS (p 0.05). Regarding the application protocols, EL and HL provided higher mean SBS than those obtained with MI (p 0.05). HL resulted in the highest mean SBS and the lowest mean nanoleakage after 18M. Conclusion: Simplified adhesives may need an extra hydrophobic resin layer to achieve a stable and durable adhesive interface. The self-etch approach should be recommended for the universal adhesive. Keywords: dental bonding, dentin bonding agents, material testing, self-etch, etch-and-rinse, hydrophobic, water storage, bond strength, nanoleakage