Objectives: To evaluate the effect of minocycline and chlorhexidine pretreatment of acidetched dentin on the longevity of resin-dentin bond strength (μTBS) and nanoleakage of twostep etch-and-rinse adhesives. Methods: Before application of Prime & Bond NT and Adper Single Bond 2 in occlusal dentin, the dentin surfaces were treated with 37% phosphoric acid, rinsed, air-dried, and rewetted with water (control group), 2% minocyc mm2) to be tested in tension (0.5 mm/min) immediately or after 24 months of water storage. For nanoleakage, two specimens of each tooth/period were immersed in the silver nitrate solution, photo-developed, and polished with SiC paper for analysis under energy-dispersive X-ray spectroscopy/scanning electron microscopy. Results: Reductions of the μTBS and increases in the nanoleakage were observed for both adhesives when the rewetting procedure was performed with water. Stable bonds were observed for the 2% minocycline and 2% chlorexidine digluconate groups after 24 months. Conclusions: The use of 2% minocycline as pretreatment of acid-etched dentin is one alternative to retard the degradation of resindentin interfaces over a 24-month period as well as 2% chlorexidine digluconate.