Structural properties and polymorphism of monoolein (MO) in aqueous solutions have been studied for a long time, and the final picture can be considered definite. The presence of bicontinuous phases and the ability to encapsulate hydrophilic, hydrophobic, and amphiphilic compounds, together with the capability to protect and slowly release the entrapped molecules, designated MO phases as good matrices for the sustained release of drugs. Because phase stability, loading efficiency, and bioavailability are strongly correlated, the interplay between MO phases and entrapped compounds is worthy of investigation. In this paper, low angle X-ray diffraction has been used to describe the effects of a model protein (the cytochrome-c) on the monoolein cubic phases as a function of both incubation time and protein concentration in the soaking solutions. Results show that the MO polymorphism is strongly modified by the protein, underlying the very large affinity of the cytochrome-c toward monoolein. However, the different phases have a different sensibility to cytochrome-c, as phase transitions occur when the protein amount exceeds some different critical values, probably related to the structure characteristics (2 cytochrome-c per unit cell at the Pn3m to Im3m cubic phase transition and 10-20 cytochrome-c per unit cell at the Im3m to P4(3)32 cubic phase transition). Moreover, although equilibration times resulted to be quite long (more than 10 days), the fraction of cytochrome-c incorporated into the MO phases is very high (up to 20% v/v inside the P4(3)32 cubic phase). Such results are intriguing: even if they may be specific to the cytochrome-c/MO case, the need of assessing the structural characteristics of lipid matrices before their use as drug delivery systems is evident.