One-step adhesives bond less effectively to enamel/dentin than do their multi-step versions. To investigate whether this might be due to phase separation between adhesive ingredients, we characterized the interaction of 5 experimental and 3 commercial self-etch adhesives with dentin using transmission electron microscopy. All adhesives were examined for homogeneity by light microscopy. Bonding effectiveness to dentin was determined with the use of a micro-tensile bond-strength protocol. The lower bond strength of the one-step adhesives was associated with light-microscopic observation of multiple droplets that disappeared slowly. Interfacial analysis confirmed the entrapment of droplets within the adhesive layer. The prompt disappearance of droplets upon application of a small amount of HEMA (2-hydroxyethyl methacrylate) or a HEMA-containing bonding agent, as well as the absence of droplets at the interface of all HEMA-containing adhesives, strongly suggests that the adhesive monomers separate from water upon evaporation of ethanol/acetone. Upon polymerization, the droplets become entrapped within the adhesive, potentially jeopardizing bond durability. This can be avoided by strong air-drying of the adhesive, thereby removing interfacial water and thus improving bonding effectiveness.