The effects of amino acids, several aromatic compounds, and peptides on the gelation and solubility of deoxyhemoglobin S have been studied. The aromatic amino acids (tryptophan, phenylalanine, and possibly tyrosine) significantly inhibited the rate of gel formation and increased solubility. The dipeptide L-Thr-L-Phe, the tripeptide L-Lys-L-Phe-L-Phe, and various phenylalanine analogues (hydrocinnamic acid, phenethylamine, benzamine, and amphetamine) also inhibited gelation. However, aromaticity is not a sufficient condition for inhibiting gelation as shown by the fact that several aromatic compounds (acetylsalicylic acid, salicyclic acid, aniline, and phenol) enhanced gelation. Surprisingly, several oligopeptides (betaS1--12, betaS4--8, betaS3--13, and betaS4--10) also enhanced gelation. All of these additives follow the supersaturation relationship that the delay time for gelation is proportional to the ratio of the total hemoglobin concentration to the solubility of deoxyhemoglobin S to the nth power (n approximately 35). A possible mechanism for the action of these inhibitors is considered in terms of a specific site of interaction on the hemoglobin molecule. Although none of these compounds may prove to be efficacious in treatment of sickle cell anemia, they should yield information about the structure and process of formation of the deoxyhemoglobin S gel.