The effect of second, third, and fifth generations of poly(propylene imine) glycodendrimers-open maltose shell (PPI-Mal) on reverse hexagonal (H-II) mesophase and on the release of sodium diclofenac (Na-DFC) drug was investigated. The H-II mesophase comprised glycerol monooleate (GMO)/tricaprylin (TAG) in a weight ratio of 90/10 and 20 wt % water (+0.5 wt % PPI-Mal of each generation) without or with 0.25 wt % (Na-DFC). The microstructural characteristics of these systems were determined by small-angle X-ray scattering; attenuated total reflectance Fourier transform infrared was used to characterize the molecular level interactions and the location of the PPI-Mal. Third-and fifth-generation PPI-Mal, because of their maltose groups, interact mainly with the bulk water within the cylinders of the H-II and strongly bind the water molecules, as manifested by the decrease in the lattice parameter and dehydration of the lipid headgroups. Co-solubilization of Na-DFC with the third and fifth generations caused competition of the two host compounds for water binding and induced relocation of the drug from the bulk water to the GMO-water interface. In vitro release of Na-DFC from the H-II showed that the release process was faster in the systems with third- and fifth-generation PPI-Mal compared with the control and second-generation systems.