To determine if adverse chemical interaction and adhesive permeability are both responsible for the incompatibility between a single-step, self-etching adhesive and chemically-cured or dual-cured composites. Bonding was performed with Xeno CF Bond (Dentsply-Sankin), on either hydrated (H) or dehydrated (DH) human dentin. For microtensile bond strength evaluation, a dual-cured hybrid composite (Bis-Core) was activated using: (1) the light-cured (L) mode (base syringe only), (2) delayed light activation (DL) (base syringe left on top of cured adhesive in the dark for 20 min before activation), and 3) the chemically-cured (C) mode (base and catalyst syringes in the dark). A chemical co-initiator (B; BondLink) was also applied to the cured adhesive before coupling with the composite in chemically-cured mode. This resulted in seven experimental groups: (1) L-H (control); (2) DL-H; (3) DL-DH; (4) C-H; (5) C-DH; (6) C-B-H; and (7) C-B-DH. For transmission electron microscopy, the dual-cured composite in the seven groups was replaced with a light-cured microfilled composite (Metafil CX) and an experimental chemically-cured microfilled composite of the same composition. Specimens were immersed in ammoniacal silver nitrate for 24 h. After reduction of the diamine silver ions to silver, undemineralized and unstained sections were examined for nanoleakage within the resin-dentin interfaces of the seven groups. For the light-cured modes, bond strengths fell substantially in DL-H but not in DL-DH. For the chemically-cured modes, bond strengths were lowest in C-H and only increased slightly in C-DH. The use of a chemical co-initiator with the adhesive further improved the bond strength in C-B-H. Only C-B-DH was not significantly different from the control light-cured mode L-H. Two abnormal modes of silver deposition were observed in resin-dentin interfaces. A continuous layer of silver was observed when the chemically-cured composite was applied to the cured adhesive in the absence of the chemical co-initiator (C-H; C-DH). Silver-impregnated water blisters were identified when the chemically-cured composite was coupled to bonded hydrated dentin (C-H; C-B-H). Similar water blisters were seen in DL-H in which adverse chemical interaction should not occur. Adverse chemical interaction between catalytic components of chemically-cured composite and the tested single-step, self-etching adhesive was the major cause of reductions in bond strength, while adhesive permeability was a minor cause of bond strength reduction. The combination of these two factors accounts for the substantial reduction in bond strength when chemically-cured or dual-cured composites were coupled to bonded hydrated dentin.