The average solution conformation of the glycosylphosphatidylinositol (GPI) membrane anchor of Trypanosoma brucei variant surface glycoprotein (VSG) has been determined by using a combination of two-dimensional 1H-1H NMR methods together with molecular orbital calculations and restrained molecular dynamics simulations. This allows the generation of a model to describe the orientation of the glycan with respect to the membrane. This shows that the glycan exists in an extended configuration along the plane of the membrane and spans an area of 600 Å2, which is similar to the cross-sectional area of a monomeric N-terminal VSG domain. Taken together, these observations suggest a possible space-filling role for the GPI anchor that may maintain the integrity of the VSG coat. The potential importance of the GPI glycan as a chemotherapeutic target is discussed in light of these observations.