Triton X-114 phase separated integral membrane proteins (IMPs) of a multidrug resistant strain of Plasmodium yoelii nigeriensis (P. yoelii) were screened for their potential to impart protection against malaria infection in BALB/c mice. As revealed by immunoblotting, antibodies present in parasite specific sera from convalescent (protected) as well as immunized (partially protected) animals recognized different membrane proteins. A thorough investigation reveals that P. yoelii specific convalescent sera recognized IMPs with molecular masses ranging from 21 to 81 kDa. Among various membrane proteins, the IMPs corresponding to 81 and 66 kDa molecular weight were highly prominent in the immunoblots probed with the sera from convalescent animals, whereas sera from immunized animals failed to produce impressive band pattern. Immunofluorescence assay revealed that the 66-kDa IMP specific antibodies reacted with fixed smears of mature schizonts and merozoites. Further immunization with 66 kDa IMP (PyIMP) purified through polyclonal IgG sepharose 4B affinity did not impart effective immune response (in its free form) and could provided partial protection only. On the other hand, animals immunized with 66 kDa PyIMP entrapped in phosphatidyl-choline/cholesterol (PC/chol) liposomes protected BALB/c mice against lethal P. yoelii challenge.