Objective: To compare changes in enamel microhardness adjacent to orthodontic brackets after using bonding agents containing various compositions of bioactive glass compared to a traditional resin adhesive following a simulated caries challenge. Materials and Methods: Extracted human third molars (n 5 10 per group) had orthodontic brackets bonded using one of four novel bioactive glass (BAG)-containing orthodontic bonding agents (BAG-Bonds) or commercially available Transbond-XT. The four new adhesives contained BAG in varying percentages incorporated into a traditional resin monomer mixture. Teeth were cycled through low-pH demineralizing and physiologic-pH remineralizing solutions once each day over 14 days. Microhardness was measured on longitudinal sections of the teeth 100, 200, and 300 mm from the bracket edge and beneath the brackets, at depths of 25 to 200 mm from the enamel surface. Normalized hardness values were compared using three-way analysis of variance. Results: Significantly less reduction in enamel microhardness was found with the experimental adhesives at depths of 25 and 50 mm at all distances from the bracket edge. In all groups, there were no significant changes in enamel microhardness past 125-mm depth. Results varied with the different BAG-Bonds, with 81BAG-Bond showing the smallest decrease in enamel microhardness. Conclusions: The BAG-Bonds tested in this study showed a reduction in the amount of superficial enamel softening surrounding orthodontic brackets compared to a traditional bonding agent. The results indicate that clinically, BAG-Bonds may aid in maintaining enamel surface hardness, therefore helping prevent white spot lesions adjacent to orthodontic brackets. (Angle Orthod. 2013;83:97-103.)