A number of protease inhibitors (PIs) are dependent on an acidic gastric pH for optimal drug dissolution and absorption. As a result, the potential for negative drug interactions with acid-reducing agents exists and could lead to subtnerapeutic drug concentrations, viral breakthrough, and development of drug resistance. Pharmacokinetic evaluations of a number of PIs given with acid-reducing agents have been performed and show varying degrees of effect. Given the possibility of decreases in PI exposures, clinicians should be aware of the potential for a negative interaction when selecting PI-based HAART for patients taking acid-reducing agents.