(1) The effect of glycophorin, a major intrinsic glycoprotein of the human erythrocyte membrane, on lipid polymorphism has been investigated by 31P-NRM (at 36.4 MHz) and be freeze-fracture electron microscopy. (2) Incorporation of glycophorin into vesicles of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) results in the formation of unilamellar vesicles ((1 000-5 000 A diameter) which exhibit 31P-NRM bilayer spectra over a wide range of temperature. A reduction in the chemical shift anisotropy ( delta sigma eff csa) and an increase in spectral linewidth in comparison to dioleoylphosphatidylcholine liposomes may suggest a decrease in phospholipid headgroup order. (3) 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), in the presence of excess water, undergoes a bilayer to hexagonal (HII) phospholipid arrangement as the temperature is increased above 0 degrees C. Incorporation of glycophorin into this system stabilizes the bilayer configuration, prohibiting the formation of the HII phase. (4) Cosonication of glycophorin with DOPE in aqueous solution (pH 7.4) produced small, stable unilamellar vesicles (300-1 000 A diameter), unlike DOPE alone which is unstable and precipitates from solution. (5) The current study demonstrates the bilayer stabilizing capacity of an intrinsic membrane protein, glycophorin, most likely by means of a strong hydrophobic interaction between the membrane spanning portion of glycophorin and the hydrophobic region of the phospholipid.