The interactions of acidic and basic drugs with alpha 1-acid glycoprotein (alpha 1-AGP) were investigated using circular dichroism (CD) measurements. Extrinsic Cotton effects were generated by the binding of drugs to alpha 1-AGP. The CD data suggested the presence of a single binding site on the alpha 1-AGP molecule. The induced ellipticities of the acidic drug-alpha 1-AGP system decreased with increasing pH, while the ellipticities for the basic drugs increased with pH. The ellipticities for all drugs were reduced by the addition of fatty acids. Furthermore, the induced ellipticities decreased in the presence of cesium chloride for basic drugs bound to alpha 1-AGP. The extrinsic Cotton effects therefore appear to result from hydrophobic interaction with alpha 1-AGP for the acidic drugs and from hydrophobic and electrostatic interactions for the basic drugs.