The present study describes the effect of saccharides on phase modulation of dehydrated cationic dimethyl-dioctadecylammonium (DDA)-based liposomes. It has been shown that saccharides such as sucrose, lactose and mannitol preserve the lipid membranes during drying. The saccharide molecules associated with polar head groups of dehydrated phospholipid bilayers by replacing the water molecules and led to stabilize the membranes. The study revealed that the addition of saccharides in the formulation demonstrated a miscible mixture that might construct a stable dried liposomal formulation. DTA analysis showed that sucrose (5%w/v) applied to DDA liposomal formulation were relatively more miscible with the lipid mixtures; whereas lactose and mannitol at the same concentration of 5% showed phase separation from the lipid mixtures in the dehydrated state and might trigger leakage that further affect the efficacy of the entrapped drug/antigen. Furthermore, XRD and SEM analysis exhibited supporting evidents in which crystallinity of the formulation using sucrose and lactose were relatively less crystalline-forming properties compared to mannitol. This might support the existence of physical interaction of saccharides with the lipid mixtures. Application of sucrose in low concentration (5%w/v) revealed the protective mechanism that was based on ‘water replacement theory’; indicated by the depressed Tm of the dried lipid mixtures. Thus, in this particular study, we suggested that the protection of liposome formulations during the drying process was involving this mechanism. Addition of saccharides in the dried DDA formulation have prospective advantages as vaccine delivery system as they have been reported stabilizing the bilayer membrane.