The properties of the complexes of ferricytochrome c with two different polyanions--poly(vinylsulfate) and poly(4-styrene-sulfonate)--with a comparable charge density but with the different size of the uncharged part of their molecules have been studied by means of optical spectroscopy, differential scanning colorimetry, and gel chromatography. Ferriccytochrome c formed a complex with the former one through coulombic interactions and remained in a native-like state. The addition of the second polyanion to a solution of ferric cytochrome c at a low ionic strength, pH 7.0, resulted in profound conformational change in the hydrophobic core of protein (opening of the heme crevice with a perturbation of the methionine 80-heme iron bond and the hydrophobic core of the protein). These may be understood as an involvement of noncoulombic (hydrophobic, H-bonding) interactions of the uncharged part of the polyanion molecule. Conformational changes and the observed shift in acidic transition from low spin to high spin state of ferric cytochrome c detected in the presence of the polyanions may have biological implication in understanding the origin of conformational changes in proteins induced in the course of their interaction with membrane lipids and membrane proteins.