To assess the biocompatibility of a third-generation dentainl adhesive that uses a smear layer conditioner (Scotchbond 2), Class V cavities were prepared and restored in vivo, following a standardized protocol, in 32 human premolars to be extracted for orthodontic reasons. Histologic observation showed seven slight, five moderate, and one severe reaction short term, while 11 slight and three moderate reactions were observed long term. It appeared that the intensity of the reactions decreased with time. Bacteria were observed on only five teeth, and no corelation could be established between the presence of bacteria and the intensity of the reactions. It seemed that the conditioning of the smear layer, although it might have rendered the residual dentin more permeable, limited percolation phenomena by increasing adhesion. Although only one severe reaction was observed, it is mandatory in a clinical setting to place a protective lining near the pulp.