Quantitative structure activity relationship (QSAR) analyses have been performed to analyze the basis for the antigelling activity of a series of aryl-substituted alanine analogs, including both phenylalanine and tryptophan analogs. We find that these two groups of compounds should be treated separately, probably due to the difference in shape between the phenyl and indole rings in the respective side chains. For the phenylalanine analogs, the hydrophobicity of the side chain, as measured by the pi constants of the aromatic ring and their substituents, explains about 50% of the variance in antigelling activity. The square of the aromatic dipole moment and the steric overlap volume, as obtained from three dimensional molecular shape analysis, account for an additional 20% and 10% of the variance, respectively. For the tryptophan analogs, the majority of the variance is explained either by the square of the aromatic dipole moment (70%) or by the steric overlap volume (60%), with the two descriptors being highly correlated. This result suggests that the tryptophan analogs exhibit a relatively tight steric fit within their binding sites. The separate QSAR's of phenylalanine and tryptophan analogs also suggest that these two groups of compounds may bind to hemoglobin through different mechanisms or at different sites. For phenylalanine analogs, the hydrophobic interaction is dominant, and the dipole-dipole interaction and steric effects contribute to lesser extents. For the tryptophan analogs, the dipole-dipole interaction prevails with a high degree of steric shape complimentarity, but without any significant contribution from hydrophobic interactions. This information should assist in the future development of more specific and effective agents.