We have investigated the ability of lipid-indinavir particles composed of 3to-1 lipid-drug molar ratio to encapsulate an aqueous marker calcein and anti-HIV drug 3 H-phosphonylmethoxypropyl-adenine (PMPA). Even at a high density of indinavir associated to lipid-indinavir nanoparticles, they form an enclosed lipid membrane that allows encapsulation of calcein and PMPA in an aqueous compartment. At neutral pH, practically all indinavir was incorporated into lipid bilayer and lipid associated indinavir can be dissociated with half-maximum pH recorded between 5.2 and 5.5. pH-Dependent release of indinavir did not influence calcein release significantly. However, pH-dependent release of indinavir affected PMPA release. By lowering pH, PMPA release was enhanced in the presence of indinavir in the lipid bilayer. Collectively, these data indicate that indinavir incorporated in lipid particles provides (1) stable bilayers capable of encapsulating other hydrophilic drugs, (2) ability to dissociate indinavir (which is acid stable) from lipid membranes, by lowering the pH, and (3) enabling enhancement in pHdependent release of aqueous contents. However, the degree of pH-dependent release could be related to the charge and size of an aqueous molecule.