The resultant increase of the solubility of hemoglobin S in the presence of various alcohols, amides, and ureas has been found to correlate with the individual partition coefficients of each agent. Comparisons have been made using the log of the slope of the curves obtained from standard ultracentrifugation gelation assays with the antisickling agents and is expressed in terms of log (slope Cs/[A]) = k log P + k' where Cs is the solubility of HbS in gm/dL, [A] is the concentration of the agent in moles/liter, P is the partition coefficient of A, and k (slope) and k' (y intercept) constants. These results are similar to other structure activity relationships developed by Corwin Hansch and co-workers [5-8, 10]. Such comparisons illustrate in part the quantitative binding capabilities of organic molecules to proteins based upon their inherent hydrophobic character which can be calculated and predicted a priori after a few initial observations. This paper demonstrates that the solubility increase of hemoglobin S by various simple alcohols, amides and ureas results directly from the hydrophobic qualities of each additive in a given series. It is further reasoned that these small molecules interact with hydrophobic areas on hemoglobin S and that this conjugal hydrophobic interaction explains in part their mechanism of action and polymer destabilization. The role of the polar group is also shown to be important for activity.