The interaction of a series of ligand molecules, all consisting of substituted benzoic and nicotinic acid derivatives, and povidone was studied. The influence of ionic strength, buffer concentration, and temperature was evaluated using factorial analysis. Complex formation was not affected at low ionic strength, but increased considerably at higher values due to dehydration of the macromolecule. Complex formation was enhanced in phosphate solutions, particularly in the presence of dibasic phosphate ions. A linear relationship was found between the logarithm of the percentage of bound ligand and ionic strength and buffer capacity. Increasing the temperature lowered complex formation. Although dehydration of the macromolecule also occurred, the decrease in complex formation could be attributed to the solubility increase of the ligand molecules. The influence of the degree of dissociation of the ligand molecules was investigated by factorial analysis. The compounds mainly interacted to a lesser extent in the dissociated than in the nondissociated state. In addition, a negative effect of a pyridine ring with respect to a phenyl ring was observed. The binding tendency was markedly increased by substituting the aromatic ring structure with hydroxyl functions and by esterification of the carboxyl function attached to the ring. The results suggested that lipophilicity and hydrogen bonding played a predominant role in povidone complexation.