β-Sheet propensities of different amino acids depend on the context of both secondary and tertiary structure. In an attempt to establish general empirical relationships that determine this context dependence, we have determined the free energy of unfolding of a series of mutants at six positions in the β-sheet of chymotrypsin inhibitor 2 (CI2). We have generated the series Val→Ala→Gly and Val↔Thr at five positions, as well as the side-chain deletion He-Val at residue 49 and Ala→Gly at residue 77. In the series Val→Ala→Gly, the ranking order in terms of stability is Val > Ala > Gly at all positions. However, the change in free energy on deletion of methylene groups varies greatly. When Val and Thr are interchanged, the wild-type residue is always the more stable, but by a different amount at each position. We have attempted to rationalize the data by relating it to changes in solvent-accessible surface area, packing density, and statistically derived pseudo-energy functions that depend on ϕ,ψ angles. There is no significant correlation of the energies with any of the variables except with the pseudo-energy function, but the deviations from these values are large. We conclude that thermodynamic scales for β-sheet propensity are currently of insufficient precision for general design purposes, although they may be useful in special cases.